Evaluation of an individualized dosing regimen of busulfan in children undergoing allogeneic haematopoietic stem cell transplantation

OBJECTIVE To assess target attainment of busulfan exposure using a new model-based dosing regimen and therapeutic drug monitoring (TDM). Busulfan is an alkylating drug used in conditioning regimens for allogeneic haematopoietic cell transplantation (allo-HCT). Its narrow therapeutic range in combination with large interindividual variability in exposure, even after intravenous administration, necessitates dose individualization. DESIGN Prospective cohort study. METHODS All children who underwent allo-HCT in 2011 or 2012 receiving busulfan-based conditioning were included. Intravenous busulfan was administered once daily on four consecutive days and drug levels were measured on days 1 and k. For each patient a 'hypothetical' exposure (cAUC) without TDM was determined by extrapolating the AUC of day 1. The 'true' cAUC was then estimated based on pharmacokinetic data obtained on days 1-4 including TDM-based dose adjustment. Means and ranges were compared between cAUCs determined with and without TDM-based dose corrections. Also target attainment rates (cAUC 80-100 mg-h/L] were compared between 'hypothetical' and 'true' exposure. RESULTS 50 patients were included. Without TDM mean cAUC was 85.3 mg-h/L versus 96.2 mg-h/L with TDM. The range in individual cAUCs was significantly larger without TDM than with TDM IP = 0.001 ). Without TDM 34% of patients reached target cAUC and with TDM this significantly increased to 70% of patients (P = 0.0011. CONCLUSION The weight-based dosing regimen overall led to a mean busulfan exposure within the target range, yet the interindividual variation was substantial. Therefore, TDM of intravenous busulfan remains recommended and is of utmost importance to reach optimal target exposure in order to optimize HCT outcomes

Dried Blood Spot Analysis: An Easy And Reliable Tool To Monitor The Biochemical Effect Of Hematopoietic Stem Cell Transplantation In Hurler Syndrome Patients In A Multi-Center International Setting

Digitalitzat per Artypla

Busulfan exposure associated with event-free survival in children after allogeneic haematopoietic stem cell transplantation: A retrospective multicenter cohort study

Busulfan exposure associated with event-free survival in children after allogeneic haematopoietic stem cell transplantation: A retrospective multicenter cohort study OBJECTIVE To determine the relationship between busulfan cumulative area under the curve (AUC] and event-free survival lEFS] in children undergoing allogeneic haematopoietic stem cell transplantation (alloHCT). DESIGN Retrospective, multicenter cohort study. METHODS Children who underwent alloHCT in 15 different centres worldwide were included in this study (2000-20131. Participants had to be on intravenous busulfan and pharmacokinetic samples had to be available. Exposure of interest was the cumulative AUC of busulfan, and primary outcome was EFS (time to graft failure, relapse or all-cause mortality). Cox regression models were used to derive relative risks (RR), and the optimal busulfan AUC level was estimated using propensity adjusted Weibull models. RESULTS A total of 674 subjects (41[%] malignant, 59[%] non- malignant) with a median age of 4.5 years (interquartile range 1.4-10.7 years) were included in the analysis. We observed a significant U-shaped relationship between busulfan cumulative AUC and EFS (P = 0.011). The optimal target was estimated at 90 mgh/L (78-101 mgh/L), and was independent of any of the investigated patient characteristics. An AUC below the target increased the risk of graft failure and relapse (relative risk 1.75, P = 0.004), while transplant-related mortality was more pronounced when the AUC was too high (relative risk 2.99, P <0.0011. CONCLUSION This is the largest study on the relationship between busulfan and clinical outcomes in children undergoing alloHCT. Our results strongly advocate the use of therapeutic drug monitoring of busulfan, using 90 mg-h/L (78-101 mg h/L) as a target

Epidemiology of Pneumocystis jirovecii Pneumonia and (Non-)use of Prophylaxis

Objectives: Pneumocystis jirovecii pneumonia (PCP) is an AIDS-defining illness. In patients with HIV, the benefit of PCP prophylaxis is well-defined when the CD4 T-cell count decreases below 200 cells/μL. In other immunocompromised patients, the value of PCP prophylaxis is not always as well-established. This study aimed to describe the epidemiology of PCP in recent years and assess how many patients with PCP did or did not receive prophylaxis in the month preceding the infection. Material and Methods: A multicenter retrospective study was performed in 3 tertiary care hospital. A list of patients that underwent broncho-alveolar lavage sampling and Pneumocystis jirovecii (PJ) PCR testing was retrieved from the microbiology laboratories. An in-house PJ quantitative PCR (qPCR) was used in each center. A cycle threshold (Ct) value of ≤ 28.5–30 was considered a probable PCP. For patients with a positive PJ qPCR but above this threshold, a predefined case definition of possible PCP was defined as a qPCR Ct value ≤ 34–35 and both of the following criteria: 1. Clinical and radiological features compatible with PCP and 2. The patient died or received PCP therapy and survived. Patient files from those with a qPCR Ct value ≤ 35 were reviewed to determine whether the patient fulfilled the case definition and if PCP prophylaxis had been used in the weeks preceding the PCP. Disease-specific guidelines, as well as hospital-wide guidelines, were used to evaluate if prophylaxis could be considered indicated. Results: From 2012 to 2018, 482 BAL samples were tested. Two hundred and four had a qPCR Ct value ≤ 35 and were further evaluated: 90 fulfilled the definition of probable and 63 of possible PCP while the remaining 51 were considered colonized. Seventy-four percentages

Rabbit ATG/ATLG in preventing graft-versus-host disease after allogeneic stem cell transplantation: consensus-based recommendations by an international expert panel

This collaborative initiative aimed to provide recommendations on the use of polyclonal antithymocyte globulin (ATG) or anti-T lymphocyte globulin (ATLG) for the prevention of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). A comprehensive review of articles released up to October, 2018 was performed as a source of scientific evidence. Fourteen clinically relevant key questions to the domains indication, administration, and post-transplant management were developed and recommendations were produced using the Delphi technique involving a Panel of 14 experts. ATG/ATLG was strongly recommended as part of myeloablative conditioning regimen prior to matched or mismatched unrelated bone marrow or peripheral blood allogeneic HSCT in malignant diseases to prevent severe acute and chronic GvHD. ATG/ATLG was also recommended prior to HLA-identical sibling peripheral HSCT with good but lesser bulk of evidence. In reduced intensity or nonmyeloablative conditioning regimens, ATG/ATLG was deemed appropriate to reduce the incidence of acute and chronic GvHD, but a higher risk of relapse should be taken into account. Recommendations regarding dose, application, and premedication were also provided as well as post-transplant infectious prophylaxis and vaccination. Overall, these recommendations can be used for a proper and safe application of polyclonal ATG/ATLG to prevent GvHD after allogeneic HSCT