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

Abstract

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.

Long-term outcome of hematopoietic stem cell transplantation for IL2RG/JAK3 SCID: a cohort report

“…The use of treosulfan-based regimens has previously been reported in patients with primary immunodeficiency with few significant short-term toxicities. [19][20][21] It is encouraging to find that treosulfan-containing low-toxicity myeloablative regimens confer improved donor chimerism. In these patients, the goal of any conditioning regimen should be to achieve .50% donor B-lymphocyte chimerism to reliably cease immunoglobulin replacement.…”

Penetration of Treosulfan and its Active Monoepoxide Transformation Product into Central Nervous System of Juvenile and Young Adult Rats

“…Very young children, as inherently susceptible to toxicity of standard myeloablative agents-busulfan and total body irradiation-are the group of HSCT patients in which TREO is supposed to be particularly useful. So far, TREO-based conditioning has been applied in patients as young as 1 month old (Slatter et al, 2011(Slatter et al, , 2015Dinur-Schejter et al, 2015). The present study was aimed at assessing penetration of TREO and its active epoxy-transformers across the BBB in 10-day-old (JR) and 34-to 35-day-old (YAR) rats and, in the latter, additionally across the BCSFB.…”

“…On the other hand, brain exposure to drugs could be associated with neurologic adverse effects, for instance seizures. Beneficially, in clinical trials high-dose TREO demonstrated low neurotoxicity in adults as well as children, at least in comparison with high-dose busulfan, requiring anticonvulsive prophylaxis (Wachowiak et al, 2011;Casper et al, 2012;Danylesko et al, 2012;Shimoni et al, 2012;Boztug et al, 2015). Nevertheless, in one pediatric study (n = 70, including 46 infants), seizures occurred in four infants aged #4 months (Slatter et al, 2011).…”

“…In the last decade the anticancer drug treosulfan (TREO) has emerged as a promising myeloablative agent used before hematopoietic stem cell transplantation (HSCT) in pediatric and adult patients (Główka et al, 2010;Nemecek et al, 2011;Slatter et al, 2011;Wachowiak et al, 2011;Casper et al, 2012;Shimoni et al, 2012;Beier et al, 2013;Dinur-Schejter et al, 2015;Boztug et al, 2015;Lawitschka et al, 2015;Strocchio et al, 2015). Currently, various clinical phase II and one phase III trials are conducted aimed at the registration of the myeloablative conditioning agent.…”

Mini Review: Screening and Management of Late Effects in Patients with Severe Combined Immunodeficiency after Allogeneic Hematopoietic Cell Transplantation

“…The development and use of alternative agents should be encouraged and will hopefully lead to decreased long-term morbidity and mortality. Treosulfan is a structural analogue to busulfan approved for use in Europe and is associated with improved short-term survival when compared to busulfan [42][43] . However, how treosulfan compares to busulfan in the long term remains to be seen.…”