The Experts below are selected from a list of 282 Experts worldwide ranked by ideXlab platform
Jeannine S Mccune - One of the best experts on this subject based on the ideXlab platform.
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myeloablative Busulfan melphalan bumel consolidation following induction chemotherapy for patients with high risk neuroblastoma a children s oncology group cog study
Journal of Clinical Oncology, 2016Co-Authors: Meaghan Granger, Jeannine S Mccune, Gregory A Yanik, Arlene Naranjo, Steven G Dubois, Rochelle Bagatell, Brian Weiss, Stephan A Grupp, Sheena C Tenney, Shahab AsgharzadehAbstract:10528Background: The COG conducted a groupwide study of a Busulfan/Melphalan (BuMel) myeloablative regimen in patients with newly diagnosed, high-risk neuroblastoma (ANBL12P1). Previously used in SIOP-EN studies, this is the first trial using BuMel following a COG induction platform. The primary objective was regimen-related toxicity, with a specific focus on pulmonary and hepatic events. Methods: Five cycles of induction were administered, followed by intravenous Busulfan (daily, days -6 to -3), melphalan (140mg/m2, day -1) and stem cell rescue. Age and weight based dosing were used for Busulfan administration. First dose Busulfan pharmacokinetics were mandated and adjustments made to target an AUC <5500 (micromole/liter)*minute. Following hematologic recovery, patients were eligible to receive external beam radiotherapy to primary and residual metastatic sites and then proceed to maintenance immunotherapy. Unacceptable pulmonary toxicity was defined as Grade 4 pulmonary events (CTCAEv.4.0). Sinusoidal O...
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Busulfan in infant to adult hematopoietic cell transplant recipients a population pharmacokinetic model for initial and bayesian dose personalization
Clinical Cancer Research, 2014Co-Authors: Jeannine S Mccune, Scott K Baker, Meagan J Bemer, Jeffrey S Barrett, Alan S Gamis, Nicholas H G HolfordAbstract:Purpose: Personalizing intravenous Busulfan doses to a target plasma concentration at steady state ( C ss ) is an essential component of hematopoietic cell transplantation (HCT). We sought to develop a population pharmacokinetic model to predict i.v. Busulfan doses over a wide age spectrum (0.1–66 years) that accounts for differences in age and body size. Experimental Design: A population pharmacokinetic model based on normal fat mass and maturation based on postmenstrual age was built from 12,380 Busulfan concentration time points obtained after i.v. Busulfan administration in 1,610 HCT recipients. Subsequently, simulation results of the initial dose necessary to achieve a target C ss with this model were compared with pediatric-only models. Results: A two-compartment model with first-order elimination best fit the data. The population Busulfan clearance was 12.4 L/h for an adult male with 62 kg normal fat mass (equivalent to 70 kg total body weight). Busulfan clearance, scaled to body size—specifically normal fat mass, is predicted to be 95% of the adult clearance at 2.5 years postnatal age. With a target C ss of 770 ng/mL, a higher proportion of initial doses achieved the therapeutic window with this age- and size-dependent model (72%) compared with dosing recommended by the U.S. Food and Drug Administration (57%) or the European Medicines Agency (70%). Conclusion: This is the first population pharmacokinetic model developed to predict initial i.v. Busulfan doses and personalize to a target C ss over a wide age spectrum, ranging from infants to adults. Clin Cancer Res; 20(3); 754–63. ©2013 AACR .
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Pharmacogenetics of Intravenous and Oral Busulfan in Hematopoietic Cell Transplant Recipients
The Journal of Clinical Pharmacology, 2010Co-Authors: Nissa Abbasi, Barbara Vadnais, Jennifer A. Knutson, David K. Blough, Edward J. Kelly, Paul V. O'donnell, H. Joachim Deeg, Matthew A. Pawlikowski, Rodney J. Y. Ho, Jeannine S MccuneAbstract:: Kinetics-based dose targeting is often conducted in hematopoietic cell transplant (HCT) patients conditioned with intravenous (IV) or oral Busulfan to lower rates of rejection, nonrelapse mortality, and relapse. Using the candidate gene approach, the authors evaluated whether Busulfan clearance was associated with polymorphisms in the genes regulating the predominant metabolizing enzymes involved in Busulfan conjugation, specifically glutathione S-transferase (GST) isoenzymes A1 (GSTA1) and M1 (GSTM1). Busulfan clearance was estimated after the morning dose on days 1, 2, and 3; each patient's average clearance was used for analyses. The average (± standard deviation) Busulfan clearance was 3.2 ± 0.56 mL/min/kg in the separate population of 95 patients who received oral Busulfan and 103 ± 24 ml/min/m(2) in the 57 patients who received IV Busulfan. Oral Busulfan clearance was associated with GSTA1 (P = .008) but not GSTM1 (P = .57) genotypes. However, among the GSTA1 haplotypes (ie, *A*A, *A*B, *B*B), there was significant overlap in the observed oral Busulfan clearance and similar rates of achieving the target Busulfan exposure. Clearance of IV Busulfan was not associated with GSTA1 (P = .21) or GSTM1 (P = .99). These data suggest that personalizing either IV or oral Busulfan dosing cannot be simplified on the basis of GSTA1 or GSTM1 genotype.
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Busulfan in hematopoietic stem cell transplant setting
Expert Opinion on Drug Metabolism & Toxicology, 2009Co-Authors: Jeannine S Mccune, Leona HolmbergAbstract:This paper focuses primarily on the data published in the last decade about the pharmacokinetics and pharmacodynamics of oral and intravenous (i.v.) Busulfan, therapeutic drug monitoring and clinical outcome in hemato-poietic stem cell transplant (HCT) patients. Busulfan is commonly used in HCT as it is toxic to the marrow. Busulfan is available as oral or i.v. formulation. The most common significant toxicity of Busulfan is sinusoidal obstruction syndrome. Even with the introduction of i.v. Busulfan, variability in the systemic concentrations of Busulfan after weight-based dosing and the association between Busulfan plasma exposure and outcome in HCT patients have led to the continued use of therapeutic drug monitoring of Busulfan. New strategies for personalizing Busulfan dosing are being studied to maximize the use of Busulfan for optimal disease control with the least toxicity to HCT patients. One such strategy currently being evaluated is if Busulfan clearance can be accurately predicted by genetic p...
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Optimal prevention of seizures induced by high-dose Busulfan.
Pharmacotherapy, 2008Co-Authors: Andrea L. Eberly, Gail D. Anderson, Joseph S. Bubalo, Jeannine S MccuneAbstract:High-dose Busulfan is frequently used in a variety of conditioning regimens for hematopoietic cell transplantation. In this setting, Busulfan has marked neurotoxicity, specifically causing seizures that generally are tonic-clonic in character. Phenytoin has been the preferred drug to treat Busulfan-induced seizures, but this practice should be reexamined in light of newer antiepileptic drugs being preferentially used by neurologists. Characteristics of ideal seizure prophylaxis include lack of overlapping toxicity with the conditioning regimen, lack of interference with engraftment of donor cells, and minimal potential for pharmacokinetic drug interactions. Based on these criteria, phenytoin is suboptimal due to possible toxicities and is especially ill suited because of its ability to induce Busulfan metabolism. It is postulated that this induction adversely affects efforts to update methods for targeting Busulfan doses to individual patients, based on recent developments in the understanding of the pharmacogenomics of Busulfan metabolism. The existing clinical data support the use of benzodiazepines, most notably clonazepam and lorazepam, to prevent Busulfan-induced seizures. The second-generation antiepileptic drug levetiracetam possesses the characteristics of optimal prophylaxis for Busulfan-induced seizures, and early data of its efficacy are promising, although further study is needed.
Imke H Bartelink - One of the best experts on this subject based on the ideXlab platform.
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effect of weight and maturation on Busulfan clearance in infants and small children undergoing hematopoietic cell transplantation
Biology of Blood and Marrow Transplantation, 2013Co-Authors: Radojka M Savic, Morton J Cowan, Christopher C Dvorak, Luis M Pereira, Imke H Bartelink, Jaap Jan Boelens, Robbert G M Bredius, Rob Wynn, Geoff D E Cuvelier, Peter J ShawAbstract:Little information is currently available regarding the pharmacokinetics (PK) of Busulfan in infants and small children to help guide decisions for safe and efficacious drug therapy. The objective of this study was to develop an algorithm for individualized dosing of i.v. Busulfan in infants and children weighing ≤12 kg, that would achieve targeted exposure with the first dose of Busulfan. Population PK modeling was conducted using intensive time-concentration data collected through the routine therapeutic drug monitoring of Busulfan in 149 patients from 8 centers. Busulfan PK was well described by a 1-compartment base model with linear elimination. The important clinical covariates affecting Busulfan PK were actual body weight and age. Based on our model, the predicted clearance of Busulfan increases approximately 1.7-fold between 6 weeks to 2 years of life. For infants age <5 months, the model-predicted doses (mg/kg) required to achieve a therapeutic concentration at steady state of 600-900 ng/mL (area under the curve range, 900-1350 μM·min) were much lower compared with standard Busulfan doses of 1.1 mg/kg. These results could help guide clinicians and inform better dosing decisions for Busulfan in young infants and small children undergoing hematopoietic cell transplantation.
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association between Busulfan exposure and outcome in children receiving intravenous Busulfan before hematologic stem cell transplantation
Biology of Blood and Marrow Transplantation, 2009Co-Authors: Imke H Bartelink, Robert G M Bredius, Svetlana V Belitser, Marit M Suttorp, Marc B Bierings, Catherijne A J Knibbe, Maarten Egeler, Arjan C Lankester, Atoine C G Egberts, Juliette ZwavelingAbstract:Abstract Busulfan, combined with therapeutic drug monitoring–guided dosing, is associated with higher event-free survival (EFS) rates due to fewer graft failures/relapses and lower toxicity. The optimal target area under the curve (AUC) and dosing schedule of intravenous Busulfan in children undergoing hematopoietic stem cell transplantation (HSCT) remain unclear, however. We conducted a retrospective analysis of the association between Busulfan exposure and clinical outcome in 102 children age 0.2 to 21 years who received Busulfan 1 or 4 times daily before undergoing HSCT (46 malignant and 56 nonmalignant indications). EFS and overall survival after a median of 2 years of follow-up were 68% and 72%, respectively. EFS was optimal when the exposure of Busulfan (AUC) was 78 mg∗h/L (95% confidence interval=74 to 82 mg∗h/L). Acute graft-versus-host disease (aGVHD) grade II–IV occurred more frequently with greater Busulfan exposure. The addition of melphalan was an independent risk factor; melphalan use combined with high Busulfan exposure (AUC > 74 mg∗h/L) was associated with high incidences of aGVHD (58%), veno-occlusive disease (66%), and mucositis grade III-IV (26%). Dosing frequency (1 or 4 times daily) was not related to any outcome. In conclusion, dose targeting of Busulfan to a narrow therapeutic range was found to increase EFS in children. Adding melphalan to optimal Busulfan exposure is associated with a high incidence of toxicity.
Olle Ringdén - One of the best experts on this subject based on the ideXlab platform.
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N-acetyl-L-cysteine does not affect the pharmacokinetics or myelosuppressive effect of Busulfan during conditioning prior to allogeneic stem cell transplantation
Bone Marrow Transplantation, 2003Co-Authors: F Sjöö, Johan Aschan, Olle Ringdén, L Barkholt, Z Hassan, M HassanAbstract:Busulfan is currently used as a main component in the conditioning regimen prior to allogeneic stem cell transplantation (SCT). Several studies have shown a correlation between exposure to Busulfan and transplantation-related liver toxicity, such as venoocclusive disease (VOD) in patients undergoing SCT. Busulfan is metabolized mainly through glutathione (GSH). During high-dose therapy, Busulfan may deplete hepatocellular levels of GSH. As part of the conditioning therapy, Busulfan is usually followed by high doses of cyclophosphamide. The activation of cyclophosphamide yields a cytotoxic metabolite, 4-hydroxy cyclophosphamide, which is highly reactive and detoxified through GSH. According to recent studies using cell lines and animal models N -acetyl- L -cysteine (NAC), a GSH precursor, does not hamper the myeloablative effect of Busulfan during conditioning. In the present study, we administered NAC during conditioning to 10 patients at risk of VOD due to pretransplant liver disorders or elevated liver enzymes. No side effects related to the NAC infusions were observed and Busulfan concentrations were not affected. All patients became pancytopenic and engrafted with 100% donor cells. None of the patients developed VOD or liver failure. Increased liver enzymes during conditioning decreased or normalized in all patients. We suggest that NAC therapy is safe and does not impair the myeloablative effect of Busulfan during conditioning prior to SCT.
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ketobemidone may alter Busulfan pharmacokinetics during high dose therapy
Therapeutic Drug Monitoring, 2000Co-Authors: Moustapha Hassan, Janolof Svensson, Ayman Alshurbaji, P Hentschke, Per Ljungman, Christina Nilsson, Johan Aschan, Olle RingdénAbstract:: The authors report a possible interaction between ketobemidone and Busulfan during myeloablative treatment of a patient with acute myeloid leukemia. At the time of admission, the patient was receiving ketobemidone 1,000 mg/d as analgesic for a rectal fissure. The patient started conditioning prior to bone marrow transplantation with Busulfan (1 mg/kg x 4 for 4 days). High Busulfan plasma concentrations were observed after the first dose and the next doses were reduced to 0.7 mg/kg. The kinetics of both drugs revealed that an increase in ketobemidone concentration was followed by an increase in Busulfan levels. Substituting ketobemidone with morphine resulted in a decrease in Busulfan concentration despite increasing the dose once more to 1 mg/kg.
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increased risk of chronic graft versus host disease obstructive bronchiolitis and alopecia with Busulfan versus total body irradiation long term results of a randomized trial in allogeneic marrow recipients with leukemia
Blood, 1999Co-Authors: Olle Ringdén, Mats Remberger, T Ruutu, J Nikoskelainen, Liisa Volin, Lars Vindelov, T Parkkali, Stig Lenhoff, Bengt Sallerfors, L MellanderAbstract:Leukemic patients receiving marrow from HLA-identical sibling donors were randomized to treatment with either Busulfan 16 mg/kg (n = 88) or total body irradiation ([TBI] n = 79) in addition to cyclophosphamide 120 mg/kg. The patients were observed for a period of 5 to 9 years. Busulfan-treated patients had an increased risk of veno-occlusive disease (VOD) of the liver (12% v 1%, P = .01) and hemorrhagic cystitis (32% v 10%, P = .003). Acute graft-versus-host disease (GVHD) was similar in the two groups, but the 7-year cumulative incidence of chronic GVHD was 59% in the Busulfan-treated group versus 47% in the TBI group ( P = .05). Death from GVHD was more common in the Busulfan group (22% v 3%, P < .001). Obstructive bronchiolitis occurred in 26% of the Busulfan patients but in only 5% of the TBI patients ( P < .01). Complete alopecia developed in 8 Busulfan patients and partial alopecia in 17, versus five with partial alopecia in the TBI group ( P < .001). Cataracts occurred in 5 Busulfan-treated patients and 16 TBI patients ( P = .02). The incidence of relapse after 7 years was 29% in both groups. Seven-year transplant-related mortality (TRM) in patients with early disease was 21% in the Busulfan group and 12% in the TBI group. In patients with more advanced disease, the corresponding figures were 64% and 22%, respectively ( P = .004). Leukemia-free survival (LFS) in patients with early disease was 68% in Busulfan-treated patients and 66% in TBI patients. However, 7-year LFS in patients with more advanced disease was 17% in the Busulfan group versus 49% in the TBI group ( P < .01). In patients with chronic myeloid leukemia (CML) in first chronic phase, 7-year LFS was 72% and 83% in the two groups, respectively.
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High Busulfan concentrations are associated with increased transplant-related mortality in allogeneic bone marrow transplant patients
Bone Marrow Transplantation, 1997Co-Authors: Per Ljungman, Olle Ringdén, M Hassan, An Békássy, G ÖbergAbstract:The aim of this study was to investigate the importance of Busulfan concentrations for short- and long-term survival in autologous (ABMT) and allogeneic (BMT) bone marrow transplant recipients. One hundred and seventy-three patients were included in the study; 87 ABMT and 85 BMT patients. All patients received Busulfan 1 mg/kg four times daily for 4 days followed by cyclophosphamide 60 mg/kg/day for 2 days. Busulfan concentrations were measured and the mean concentration calculated for each patient. There was no difference in Busulfan concentrations between BMT and ABMT patients. Patients who died before day 100 had significantly higher Busulfan concentrations than patients surviving beyond day 100 (719 ng/ml vs 589 ng/ml; P
Mohammed Al-za’abi - One of the best experts on this subject based on the ideXlab platform.
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Busulfan clearance does not predict the development of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation
International Journal of Hematology, 2020Co-Authors: Bushra Salman, Murtadha Al-khabori, Mohammed Al-huneini, Abdulhakeem Al-rawas, David Dennison, Mohammed Al-za’abiAbstract:Hepatic veno-occlusive disease (VOD) is a life-threatening complication following hematopoietic stem cell transplant (HSCT). Busulfan has a narrow therapeutic index and its concentration was found to correlate with VOD. Our primary objective was to assess the association between Busulfan clearance and VOD in HSCT patients. In this retrospective analysis, we included patients who received their HSCT between 2003 and 2014 and followed at Sultan Qaboos University Hospital. All patients who received dose-targeted Busulfan-containing conditioning were included. Target steady-state concentration (Css) was 800–900 ng/ml. VOD was assessed using modified Seattle criteria. The impact of Busulfan clearance on VOD was analyzed using univariable logistic regression model. Seventy-three patients were included with a mean age of 15 years. Of those, 47% were transplanted for hematological malignancies and 53% for inherited hemoglobinopathies. Target Css was achieved in 85% of patients. The rate of VOD was 17%. There was no significant impact of Busulfan clearance ( p = 0.919) or area-under-the-concentration–time-curve ( p = 0.275) on VOD. Targeting Busulfan Css into narrow therapeutic range may have accounted for the findings. The risk of VOD might be related to other factors such as the genetic background, and more studies are required to investigate these factors.
Ruth Ladenstein - One of the best experts on this subject based on the ideXlab platform.
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Busulfan and melphalan versus carboplatin etoposide and melphalan as high dose chemotherapy for high risk neuroblastoma hr nbl1 siopen an international randomised multi arm open label phase 3 trial
Lancet Oncology, 2017Co-Authors: Ruth Ladenstein, Ulrike Potschger, Andrew D J Pearson, Penelope Brock, Roberto Luksch, Victoria Castel, Isaac Yaniv, Vassilios Papadakis, Genevieve LaureysAbstract:Summary Background High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with Busulfan and melphalan compared with carboplatin, etoposide, and melphalan. Methods We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at 128 institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared. Patients (age 1–20 years) with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate disease response. Patients were randomly assigned (1:1) to Busulfan and melphalan or to carboplatin, etoposide, and melphalan by minimisation, balancing age at diagnosis, stage, MYCN amplification, and national cooperative clinical group between groups. The Busulfan and melphalan regimen comprised oral Busulfan (150 mg/m 2 given on 4 days consecutively in four equal doses); after Nov 8, 2007, intravenous Busulfan was given (0·8–1·2 mg/kg per dose for 16 doses according to patient weight). After 24 h, an intravenous melphalan dose (140 mg/m 2 ) was given. Doses of Busulfan and melphalan were modified according to bodyweight. The carboplatin, etoposide, and melphalan regimen consisted of carboplatin continuous infusion of area under the plasma concentration–time curve 4·1 mg/mL per min per day for 4 days, etoposide continuous infusion of 338 mg/m 2 per day for 4 days, and melphalan 70 mg/m 2 per day for 3 days, with doses for all three drugs modified according to bodyweight and glomerular filtration rate. Stem-cell rescue was given after the last dose of high-dose chemotherapy, at least 24 h after melphalan in patients who received Busulfan and melphalan and at least 72 h after carboplatin etoposide, and melphalan. All patients received subsequent local radiotherapy to the primary tumour site followed by maintenance therapy. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17. Findings Between June 24, 2002, and Oct 8, 2010, 1347 patients were enrolled and 676 were eligible for random allocation, 598 (88%) of whom were randomly assigned: 296 to Busulfan and melphalan and 302 to carboplatin, etoposide, and melphalan. Median follow-up was 7·2 years (IQR 5·3–9·2). At 3 years, 146 of 296 patients in the Busulfan and melphalan group and 188 of 302 in the carboplatin, etoposide, and melphalan group had an event; 3-year event-free survival was 50% (95% CI 45–56) versus 38% (32–43; p=0·0005). Nine patients in the Busulfan and melphalan group and 11 in the carboplatin, etoposide, and melphalan group had died without relapse by 5 years. Severe life-threatening toxicities occurred in 13 (4%) patients who received Busulfan and melphalan and 29 (10%) who received carboplatin, etoposide, and melphalan. The most frequent grade 3–4 adverse events were general condition (74 [26%] of 281 in the Busulfan and melphalan group vs 103 [38%] of 270 in the carboplatin, etoposide, and melphalan group), infection (55 [19%] of 283 vs 74 [27%] of 271), and stomatitis (138 [49%] of 284 vs 162 [59%] of 273); 60 (22%) of 267 patients in the Busulfan and melphalan group had Bearman grades 1–3 veno-occlusive disease versus 21 (9%) of 239 in the carboplatin, etoposide, and melphalan group. Interpretation Busulfan and melphalan improved event-free survival in children with high-risk neuroblastoma with an adequate response to induction treatment and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. Busulfan and melphalan should thus be considered standard high-dose chemotherapy and ongoing randomised studies will continue to aim to optimise treatment for high-risk neuroblastoma. Funding European Commission 5th Framework Grant and the St Anna Kinderkrebsforschung.
