Showing papers by "Michel A. Duchosal published in 2013"

Haematopoietic stem cell transplantation: activity in Switzerland compared with surrounding European countries

Abstract: Haematopoietic stem cell transplantation (HSCT) is a highly specialised procedure used to treat malignancies of the lymphohaematopoietic system as well as some acquired and inherited disorders of the blood. This analysis by the Swiss Blood Stem Cell Transplantation Group, based on data from 2008-2011, describes, treatment rates in Switzerland for specific indications and compares this with data from Germany, France, Italy and the Netherlands, corrected for the size of the population. Differences in transplant rates, in rates for particular indications, and in the use of specific transplant technologies such as use of unrelated donors, use of cord blood or mismatched family donors are described. These data are put in correlation with donor availability from international registries and with number of transplant teams and number of procedures per team all corrected for population size.

Myélome multiple: diagnostic et perspectives thérapeutiques

Abstract: Le myélome multiple (MM) est le second cancer hématologique le plus fréquent. Il représente environ 1% de tous les cancers. L’incidence annuelle moyenne du MM en Europe est de 6/100 000/an. L’âge moyen des patients au diagnostic se situe aux environs de 65 −70 ans. L’incidence du MM augmente en fonction de l’âge, elle atteint jusqu’à 46/100 000/an chez les patients ≥75 ans, et seuls 37% des patients ont moins de 65 ans au diagnostic. Ce cancer est plus fréquent chez l’homme que chez la femme (1,4:1) et touche aux Etats-Unis deux fois plus la population afro-américaine. En dehors d’une exposition à de fortes doses de radiations ionisantes, aucun facteur prédisposant n’a été clairement identifié. Il existe des cas familiaux mais ces derniers sont exceptionnels. Le MM est invariablement précédé par une gammapathie monoclonale, or cette anomalie biologique n’est que rarement détectée préalablement au diagnostic [2]. En revanche, la présence d’une gammapathie monoclonale de signification indéterminée (MGUS), présente chez 3−4% de la population générale, ne suffit pas à elle seule à déclencher un myélome multiple. En effet, la progression en MM ne survient qu’à une fréquence moyenne de 1% par an. Les critères de diagnostic de la MGUS sont illustrés dans le tableau 1 .

Clinical pharmacokinetics of imatinib and its therapeutic relevance

Abstract: The pharmacokinetic profile of imatinib has been assessed in healthy subjects and in population studies among thousands of patients with CML or GIST. Imatinib is rapidly and extensively absorbed from the GI tract, reaching a peak plasma concentration (Cmax) within 1-4 h following administration. Imatinib bioavailability is high (98%) and independent of food intake. Imatinib undergoes rapid and extensive distribution into tissues, with minimal penetration into the central nervous system. In the circulation, it is approximately 95% bound to plasma proteins, principally α1-acid glycoprotein (AGP) and albumin. Imatinib undergoes metabolism in the liver via the cytochrome P450 enzyme system (CYP), with CYP3A4 being the main isoenzyme involved. The N-desmethyl metabolite CGP74588 is the major circulating active metabolite. The typical elimination half-life for imatinib is approximately 14-22 h. Imatinib is characterized by large inter-individual pharmacokinetic variability, which reflects in a wide spread of concentrations observed under standard dosage. Besides adherence, several factors have been shown to influence this variability, especially demographic characteristics (sex, age, body weight and disease diagnosis), blood count characteristics, enzyme activity (mainly CYP3A4), drug interactions, activity of efflux transporters and plasma levels of AGP. Additionally, recent retrospective studies have shown that drug exposure, reflected in either the area under the concentration-time curve (AUC) or more conveniently the trough level (Cmin), correlates with treatment outcomes. Increased toxicity has been associated with high plasma levels, and impaired clinical efficacy with low plasma levels. While no upper concentration limit has been formally established, a lower limit for imatinib Cmin of about 1000 ng/mL has been proposed repeatedly for improving outcomes in CML and GIST patients. Imatinib is licensed for use in chronic phase CML and GIST at a fixed dose of 400 mg once daily (600 mg in some other indications) despite substantial pharmacokinetic variability caused by both genetic and acquired factors. The dose can be modified on an individual basis in cases of insufficient response or substantial toxic effects. Imatinib would, however, meet traditional criteria for a therapeutic drug monitoring (TDM) program: long-term therapy, measurability, high inter-individual but restricted intra-individual variability, limited pharmacokinetic predictability, effect of drug interactions, consistent association between concentration and response, suggested therapeutic threshold, reversibility of effect and absence of early markers of efficacy and toxic effects. Large-scale, evidence-based assessments of drug concentration monitoring are therefore still warranted for the personalization of imatinib treatment.

Multiples Myelom: Diagnostik und therapeutische Perspektiven

Abstract: Das Multiple Myelom (MM) ist mit etwa 1% aller Krebs­ fälle die zweithäufigste hämatologische Krebserkran­ kung. Die durchschnittliche jährliche Inzidenz des MM in Europa liegt bei 6/100 000/Jahr. Das Durchschnittsalter der Patienten bei Diagnosestellung liegt bei etwa 65− 70 Jahren. Die Inzidenz des MM steigt mit zunehmendem Alter und erreicht bis zu 46/100 000/Jahr bei Patienten ≥75 Jahren; nur 37% der Patienten sind bei Diagnose­ stellung unter 65 Jahren. Männer sind häufiger betrof­ fen als Frauen (1,4:1), und in den USA ist diese Krebs­ art unter der afroamerikanischen Bevölkerung doppelt so stark verbreitet. Abgesehen von der Exposition gegenüber hohen Dosen ionisierender Strahlung gibt es keinen eindeutig identi­ fizierten prädisponierenden Faktor. Es gibt Fälle mit fa­ miliärer Häufung, diese bilden aber die Ausnahme. Dem MM geht stets eine monoklonale Gammopathie voraus, jedoch wird diese biologische Anomalie vor Dia­ gnosestellung nur selten entdeckt [2]. Das Vorliegen einer monoklonalen Gammopathie unklarer Signifikanz (MGUS) hingegen, die bei 3−4% der Gesamtbevölkerung anzutref­ fen ist, reicht allein noch nicht, um ein Multiples Myelom auszulösen. Die Progression zum MM erfolgt tatsächlich nur in durchschnittlich jährlich 1% der Fälle. Die Krite­ rien zur Diagnose der MGUS sind in Tabelle 1 darge­ stellt.