Ludmila Malásková

Monitoring trough voriconazole plasma concentrations in haematological patients: real life multicentre experience.

The objective of this retrospective study was to evaluate results from voriconazole therapeutic drug monitoring (TDM) in haematological patients in routine clinical practice. Between 2005 and 2010, 1228 blood samples were obtained from 264 haematological patients (median 3 samples/patient; range 1–27) receiving voriconazole for targeted/preemptive treatment of invasive aspergillosis (IA) (46.3% of samples), empirical therapy (12.9%) or prophylaxis (40.8%). A high‐pressure liquid chromatography assay was used to analyse voriconazole concentrations. Clinical and laboratory data were analysed retrospectively. The median of the detected voriconazole plasma concentration was 1.00 μg ml−1 (range <0.20–13.47 μg ml−1). Significant inter‐ and intra‐patients variability of measured concentrations (81.9% and 50.5%) were identified. With the exception of omeprazole administration, there was no relevant relationship between measured voriconazole concentrations and drug dose, route administration, age, gender, CYP2C19*2 genotype, gastrointestinal tract abnormality, administration via nasogastric tube, serum creatinine, and liver enzymes. However, per patient analysis identified significant role of individual voriconazole dose and drug form change on measured plasma concentration. Measured voriconazole concentrations did not correlate with the treatment outcome of patients with IA. We only identified a limited number of adverse events related to voriconazole therapy; however, the median plasma concentration was not different from concentrations measured in samples without reported toxicity. Our retrospective study has suggested that routine monitoring of voriconazole plasma concentrations has probably only a limited role in daily haematological practice.

Mechanism of impaired glucose metabolism during nilotinib therapy in patients with chronic myelogenous leukemia

Hyperglycemia represents frequent adverse event reported in chronic myelogenous leukemia (CML) patients treated with nilotinib. In order to determine the major mechanism of glucose metabolism impairment, we performed a metabolic analysis using an oral glucose tolerance test as well as assessment of incretins and adipokines at baseline and after 3 months of nilotinib treatment in patients with CML. We proved that rapid insulin resistance, compensatory hyperinsulinaemia, and hypoadiponectinaemia develop after initiation of nilotinib therapy, which clarifies not only the mechanism of impaired glucose metabolism, but also explains the fast development of dyslipidaemia and peripheral artery occlusion in nilotinib-treated CML patients.

Successful therapy with ABLC, surgery and posaconazole for Rhizopus microsporus var. rhizopodiformis liver eumycetoma in a child with acute leukaemia

Invasive fungal infection negatively influences the morbidity and mortality in heavily immuno‐incompetent patients. Diagnosis of non‐Aspergillus mould infections remains challenging despite application of a wide spectrum of non‐culture‐based microbiological techniques. Invasive diagnostic procedures are often essential. In this article, we present the case of a 15‐month‐old boy diagnosed with Rhizopus microsporus var. rhizopodiformis liver mycetoma during induction chemotherapy for acute promyelocytic leukaemia. Following surgery, he was effectively treated with a combination of ABLC and posaconazole during ongoing intensive chemotherapy. Posaconazole was also used as long‐term secondary prophylaxis.

No clinical evidence for performing trough plasma and intracellular imatinib concentrations monitoring in patients with chronic myelogenous leukaemia

This multicentre study focused on monitoring imatinib mesylate (IMA) trough plasma (Ctrough) and intracellular (IMA Cintrac) concentrations in 228 chronic myelogenous leukaemia patients. The median of measured IMA Ctrough in our patient group was 905.8 ng ml (range: 27.7–4628.1 ng/ml). We found a correlation between IMA Ctrough and alpha 1‐acid glycoprotein plasma concentrations (rS = 0.42; p < 0.001). All other analysed parameters revealed only weak (gender, dose of IMA per kg) or not significant (age, albumin, creatinine plasma concentration or body mass index) impact on measured IMA Ctrough. The IMA Ctrough decreased during the first 6 months and significantly increased later during treatment. The IMA Ctrough at the first month of therapy did not differ between patients with and without an optimal response at the 12th (p = 0.724) and 18th month (p = 0.135) of therapy. There were no significant differences in medians of IMA Ctrough between both groups measured during the first year of treatment. The IMA Cintrac during the first month were not different between patients with and without an optimal response at the 6th (p = 0.273) and the 12th month (p = 0.193) of therapy. Our data obtained from real life clinical practice did not find a benefit of routine and regular IMA Ctrough nor IMA Cintrac therapeutic drug monitoring in chronic myelogenous leukaemia patients or for subsequent adjustments of the IMA dose based on these results. Moreover, actual alpha 1‐acid glycoprotein plasma concentration should be used for proper interpretation of IMA Ctrough results. Copyright

Insulin resistance is an underlying mechanism of impaired glucose metabolism during nilotinib therapy: Correspondence

Impaired glucose metabolism (IGM) with hyperglycemia represents one of the most frequently observed adverse events (AE) during nilotinib therapy of chronic myeloid leukemia (CML). The exact mechanism of IGM remains controversial. Although a case report has shown a decrease in insulin secretion1 , our previous pilot data suggested development of insulin resistance as a possible mechanism.2 In this prospective study we aimed to confirm results from our pilot study using a larger cohort of CML patients treated with nilotinib and to compare results with data obtained on control groups receiving imatinib and dasatinib.