Personalized busulfan and treosulfan conditioning for pediatric stem cell transplantation: the role of pharmacogenetics and pharmacokinetics

Brink, Marloes H. ten; Zwaveling, J.; Swen, Jesse J.; Bredius, Robbert G. M.; Lankester, Arjan C.; Guchelaar, Henk‐Jan

doi:10.1016/j.drudis.2014.04.005

Cited by 57 publications

(67 citation statements)

References 93 publications

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“…Prospective studies will be required comparing treosulfan with low-dose busulfan-based regimens, but will need to have lengthy follow-up to determine any differences in chimerism and long-term toxicity. Further studies are also needed to evaluate the pharmacokinetics of treosulfan to determine any correlation with area under the curve and donor chimerism, 19 and finally, studies are required to evaluate long-term toxicity, particularly looking at gonadal function. Results given in absolute number and percentage over the 64 patients with available split chimerism.…”

Section: Discussionmentioning

confidence: 99%

“…[14][15][16][17][18] It has a low-toxicity profile, with the most commonly reported acute toxicities being skin, including nappy rash; diarrhea; mucositis; and hepatic toxicity; however, these are generally mild, and importantly, venoocclusive disease (VOD) is very rare. 19 Long-term effects are not welldocumented because of the relatively recent introduction of the drug for conditioning for HSCT.…”

Section: Introductionmentioning

confidence: 99%

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Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience

Morillo-Gutierrez

Beier

Rao

et al. 2016

Blood

121

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Key Points• Treosulfan, a low-toxicity alkylating agent, can be used effectively as part of conditioning for HSCT in children with CGD.• Long-term follow-up is required to ascertain effects, particularly on gonadal function and compare with other regimens.Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan-based conditioning in HSCT for pediatric patients with CGD. (IQR, and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfancontaining conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the longterm outcome, particularly on fertility. (Blood. 2016;128(3):440-448)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience

Morillo-Gutierrez

Beier

Rao

et al. 2016

Blood

121

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“…This was echoed by Nath et al [25], who observed a coefficient of variation of 35% in the clearance of busulfan in 40 children. Although some of this variability may be partially explained by pharmacokinetic polymorphisms, the data supporting this have been inconsistent [26][27][28].…”

Section: Discussionmentioning

confidence: 91%

Performance of Busulfan Dosing Guidelines for Pediatric Hematopoietic Stem Cell Transplant Conditioning

Zao

Schechter

Liu

et al. 2015

Biology of Blood and Marrow Transplantation

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Achievement of a busulfan area-under-the-concentration versus time curve (AUC) of 900 to 1500 μM·min is associated with improved hematopoietic stem cell transplant (HSCT) outcomes. Multiple pediatric busulfan dosing guidelines aim to achieve this target. The authors' objective was to describe the AUCs achieved after simulated dosing using available pediatric i.v. busulfan dosing guidelines. The health records of children who received i.v. busulfan for HSCT conditioning at The Hospital for Sick Children were reviewed. Busulfan AUCs were calculated for each patient based on plasma busulfan concentrations using either a 1-compartment model or a validated limited-sampling strategy. Published pediatric busulfan dosing guidelines were identified. Initial busulfan doses were determined for all patients using each dosing guideline and total body weight (TBW). For overweight patients (TBW-to-ideal body weight [IBW] ≥ 1.25), initial busulfan doses were also determined using IBW and adjusted IBW (IBWadj). The resulting AUCs were simulated. The proportion of subjects (TBW/IBW < 1.25, TBW/IBW ≥ 1.25, and infants) with an AUC within target (900 to 1500 μM·min) after dosing simulation with each guideline was compared. One hundred eleven children (mean age, 6.2 years [SD, ±5.2]) who received i.v. busulfan were included. When dosing with each of the 12 i.v. busulfan dosing guidelines identified was simulated using TBW in 97 non-overweight patients, the proportion of patients with an AUC within the target range varied from 51% to 74% and from 45% to 64% in infants. Use of IBW or IBWadj to calculate initial busulfan doses in overweight children improved the performance of most guidelines. Current busulfan dosing guidelines vary in their ability to achieve AUCs within the target range. For children who are not overweight, we recommend 1 of 3 high-performing guidelines that allow individualization of the target busulfan AUC. Use of either IBW or IBWadj in overweight children improves the performance of most guidelines. Regardless of the guideline used, therapeutic drug monitoring is essential to verify achievement of the target AUC.

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“…Owing to its' myeloablative and immunosuppressive properties, it has been shown to provide effective haematopoietic stem cell transplant (HSCT) conditioning with reduced risk of toxicities, in particular veno-occlusive disease (VOD), compared with traditional combinations of busulfan and cyclophosphamide. 1,2 It was first used in an HSCT setting in a group of adult patients with haematologic malignancies considered ineligible for other myeloablative preparative regimens in combination with either cyclophosphamide 3 or fludarabine. 4 Good outcomes with respect to toxicity, achievement of complete donor chimerism, low GvHD rate and low treatment-related mortality and relapse rates were shown.…”

Section: Introductionmentioning

confidence: 99%

Treosulfan-based conditioning regimens for allogeneic haematopoietic stem cell transplantation in children with non-malignant diseases

Boztug

Pötschger

et al. 2015

Bone Marrow Transplant

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An increasing number of children with non-malignant diseases can be cured by allogeneic haematopoietic stem cell transplantation (HSCT). Treosulfan (L-treitol-1,4-bis-methanesulfonate) is being used more frequently for conditioning, owing to its' lower toxicity profile compared with conventional myeloablative regimens. A retrospective analysis was performed of children registered in the EBMT database, who received treosulfan before HSCT between January 2005 and 2010, to identify possible doserelated toxicity and determine the incidence of engraftment, treatment-related mortality and overall survival (OS). Results from 316 transplants from 11 different countries are presented. Ninety-five (30%) were under 1 year of age at the time of transplant. OS was 83% and event-free survival was 76%; 3-year OS and event-free survival of infants below 1 year were 79% and 73%, respectively. No association was found with age at transplant, dose of treosulfan given, other agents used in combination with treosulfan, donor type, stem cell source, or second or subsequent transplant. In this report of the largest number of children to date receiving treosulfan for non-malignant diseases, treosulfan is shown to be a safe and effective agent even for those under 1 year of age at the time of transplant. Further prospective studies are needed using precisely defined protocols with pharmacokinetic monitoring and detailed chimerism analysis. In addition, long-term studies will be vital to determine long-term effects, for example, on fertility in comparison with other regimens.

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Personalized busulfan and treosulfan conditioning for pediatric stem cell transplantation: the role of pharmacogenetics and pharmacokinetics

Cited by 57 publications

References 93 publications

Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience

Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience

Performance of Busulfan Dosing Guidelines for Pediatric Hematopoietic Stem Cell Transplant Conditioning

Treosulfan-based conditioning regimens for allogeneic haematopoietic stem cell transplantation in children with non-malignant diseases

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