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Summary:In order to control busulfan pharmacokinetic variability and toxicity, a specific monitoring protocol was instituted in our bone marrow transplant BMT paediatric patients including a test dose, daily Bayesian forecasting of busulfan plasma levels, and Bayesian individualization of busulfan dosage regimens. Twenty-nine children received BMT after a busulfan-based conditioning regimen. Individual pharmacokinetic parameters were obtained following a 0.5 mg/kg test dose and were used for daily individualization of dosage regimens during the subsequent 4-day course of treatment. Doses were adjusted to reach a target mean AUC per 6 h between 4 and 6 g.h.ml ؉1. Plasma busulfan assays were performed by liquid chromatography. Pharmacokinetic analysis used the USC*PACK software. The performance of the test dose to predict AUC during the busulfan regimen was evaluated. Incidence of toxicity, chimerism and relapse, overall Kaplan-Meier survival, and VOD-free survival were compared after matching our patients (group A) with patients conditioned by using standard doses of busulfan (group B). Busulfan doses were decreased in 69% of patients compared to conventional doses. Expected AUC was significantly correlated with observed AUC and predictability of the test dose was 101.9 ؎ 17.9%. Incidence of VOD in group A was 3.4% vs 24.1% in group B, while the incidence of stomatitis was similar. Engraftment was successful in all patients in group A. The rate of full engraftment at 3 months post-BMT was higher in group A (P = 0.012). Long-term overall survival did not differ between the two groups, in contrast to the 90-day survival. VOD-free survival was higher in group A (P ‫؍‬ 0.026). Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving clinical outcome and reducing early mortality in

The aim of this study was to identify the risk factors for acute graft-versus-host disease (aGVHD) in children transplanted from a matched-sibling donor (MSD) or an unrelated donor (UD). In all, 87 children consecutively underwent allogeneic bone marrow transplantation (BMT) from MSD (n=36), and UD (n=51). GVHD prophylaxis included CsA alone (n=33) or with MTX (n=51). ATG was added in UD-BMT and thalassemic recipients. CsA whole-blood concentrations were measured by EMIT and the dosing regimen was monitored by Bayesian pharmacokinetic modelling. Trough blood concentration (TBC) during the first 2 weeks post transplantation was lower in children who developed grade II-IV aGVHD than those developing no GVHD or only grade I (57+/-9 vs 94+/-8 ng/ml, P=0.007), whereas peak blood concentration and area under concentration curve vs time were similar in both groups. TBC <85 ng/ml and 'use of MTX' were associated with aGVHD in MSD-SCT (P=0.003 and 0.007, respectively) as well as in UD-SCT (P=0.006 and 0.003). Donor age >or=8 years was significant only in MSD-BMT. Our results have shown the significant decisive role of pharmacological factors such as CSA TBC or use of MTX in the occurrence of GVHD in MSD as well as in UD paediatric BMT.

The ICER of TTF therapy at first-line treatment is far beyond conventional thresholds due to the prohibitive announced cost of the device. Strong price regulation by health authorities could make this technology more affordable and consequently accessible to patients.

BACKGROUND AND PURPOSE:Despite the improvement in technology, endovascular treatment of bifurcation intracranial wide-neck aneurysms remains challenging, mainly due to the difficulty of maintaining coils within the aneurysm sac without compromising the patency of bifurcation arteries. The Woven EndoBridge (WEB) device is a recent intrasaccular braided device specifically dedicated to treating such aneurysms with a wide neck by disrupting the flow in the aneurysmal neck and promoting progressive aneurysmal thrombosis.

Summary:In order to determine optimal CsA trough blood concentrations (TBC) in the early post transplantation period, we analysed relationships between TBC and acute graft-versus-host disease (aGVHD) in paediatric SCT. A total of 94 children consecutively underwent allogeneic stem cell transplantation (SCT) from: matched-sibling (MSD) (n ¼ 36), mismatched-related (MMRD) (n ¼ 3) and unrelated donors (UD) (n ¼ 55). GVHD prophylaxis usually included CsA alone or with methotrexate. Antithymocyte globulin was added in UD-SCT. TBC during the first weeks of post transplantation were estimated retrospectively by a Bayesian pharmacokinetic method and statistically associated with aGVHD. In MSD-SCT, the mean TBC during the first 2 weeks post transplantation were 42710 and 9077 ng/ml, respectively, in patients with grade II-IV and 0-I aGVHD (P ¼ 0.001). In SCT from UD and MMRD, TBC were 7374 vs 9578 ng/ml (P ¼ 0.284). For TBC 485 ng/ml, no patient developed grade II-IV aGVHD, 10 developed mild aGVHD and 30 had no aGVHD. For TBC o65 ng/ ml, 7/11 patients receiving an MSD-SCT and 4/18 receiving an UD-or MMRD-SCT developed grade II-IV aGVHD. The mean TBC corresponding to each grade were: no GVHD: 101710 ng/ml, mild: 77711 ng/ml, moderate: 61713 ng/ml, severe: 56715 ng/ml (Po0.001). These results reveal a strong relationship between TBC during the early post transplantation period and the severity of aGVHD in paediatric SCT. Bone Marrow Transplantation (2003) 32, 777-784. doi:10.1038/sj.bmt.1704213 Keywords: acute GVHD; stem cell transplantation; cyclosporine; paediatrics; Bayesian modelling Allogeneic stem cell transplantation (SCT) is curative in several malignant haematological diseases, aplastic anaemia, inborn errors of metabolism and immunodeficiencies. Unfortunately, the success of allogeneic SCT is offset by leukaemia relapses and transplant-related mortality (TRM) due to graft-versus-host disease (GVHD), toxicity of the conditioning regimen and infectious complications. Numerous risk factors for the development of acute GHVD (aGVHD) have been identified. 1-4 Even if there have recently been many advances in prophylaxis, aGVHD continues to account for significant morbidity and mortality after BMT. 3,4 Although aGVHD is less frequent 1 and less severe 5 in younger patients than in adults, grade II-IV aGVHD incidence was 35% in paediatric-matched sibling donor-BMT (MSD-BMT), using a fixed cyclosporine A (CsA) dosing regimen. 5 The risk of aGVHD is strongly increased in paediatric unrelated donor-BMT (UD-BMT) requiring intensive immunosuppressive therapy. 6 However, Souillet et al 7 reported only 26% of grade II-IV aGVHD using in vivo T-cell depletion associated with CsA and MTX, despite a majority of HLA-mismatched donors in their cohort.Although aGVHD can result in mortality, the major cause of failure and death following paediatric SCT for malignant disease, is leukaemia relapse: relapse rate (RR) reaches 41% in MSD-BMT using a fixed CsA regimen (3 mg/kg/day intravenously followed by 6 mg/kg/day orally) 8 and 37% in UD...

Lenalidomide is an immunomodulatory drug derived from thalidomide. It was developed to maximize the anti-inflammatory and anti-neoplasic properties of thalidomide and to reduce its toxicity. The molecular mechanism of action of lenalidomide is unclear, but its therapeutic activity is mainly due to its well defined antiinflammatory, immunomodulatory, anti-proliferative and anti-angiogenic properties. In relapsed or refractory multiple myeloma (MM), lenalidomide, combined with standard dose dexamethasone, is superior to dexamethasone alone in terms of time to progression, response rate and overall survival. The most commonly reported adverse events include haematological toxicity with manageable neutropenia and thrombopenia. Lenalidomide does not trigger the limiting toxicities of thalidomide: somnolence, neuropathy and constipation. Lenalidomide, in combination with dexamethasone, is indicated for the treatment of MM patients who have received at least one prior therapy and is administered orally at the dose of 25 mg q.d. for 21 days of 28-day cycles. The drug is being investigated for the treatment of newly diagnosed MM. In this review, we summarize the pharmacokinetic, pharmacodynamic and clinical trial data on lenalidomide.

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