Treosulfan-based preparative regimens for allo-HSCT in childhood hematological malignancies: a retrospective study on behalf of the EBMT pediatric diseases working party

Abstract

This retrospective analysis evaluated 51 children (0.7-17 years; median eight) with high-risk or advanced hematological malignancies, including 18 (35%) patients undergoing second/third hematopoietic SCT (allo-HSCT), not eligible for standard myeloablative regimens and transplanted from matched sibling (MSD) (n ¼ 24) or matched unrelated (MUD) (n ¼ 27) donors. Preparative regimens were based on treosulfan (TREO) i.v., a structural analog of BU, given at total dose of 30 g/m 2 (n ¼ 21) or 36-42 g/ m 2 (n ¼ 30) in combination with, fludarabine, cyclophosphamide, melphalan and/or VP-16 according to diagnosis, and risk factors. Deaths due to early regimenrelated toxicity (RRT) did not occur. Nonrelapse mortality was 8% at 1 year and 16% after 4 years. Myeloid engraftment was achieved in 94%, complete donor chimerism in 90% of patients. A 4-year incidence of relapse was 24%, and was significantly lower after MUD-HSCT (8%) than after MSD-HSCT (39%), but similar in children undergoing first (28%) or second/third HSCT (17%). A 4-year disease-free survival was 61%, but it was significantly better in myeloid (73%), than in lymphoid malignancies (41%). Thus, children with high-risk and advanced hematological malignancies and high-risk of life-threatening RRT can be transplanted effectively and safely using TREO-based regimens. Particularly favorable results were achieved in myeloid malignancies and in children undergoing second HSCT.

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

“…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.…”

Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis

“…10 Treosulfan has previously been proven to be a safe and effective conditioning agent for malignant and non-malignant disease. 8,13,14 However, previous experience with treosulfan, fludarabine, and alemtuzumab in HLH was anecdotal. In a series of immunodeficiencies, 3 of 4 HLH patients died, 15 whereas 2 patients in another cohort are long-term survivors.…”

Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan

“…[6][7][8][9] These results have been confirmed recently in pediatric patients with high-risk hematologic malignancies receiving a treosulfan-based preparative regimen before second or third HSCT. 10 Moreover, a treosulfanbased conditioning regimen proved to be valuable in children with primary immunodeficiencies. 11 We reported recently preliminary, encouraging results on the use of a thiotepa/treosulfan/fludarabine myeloablative regimen in a cohort of 20 patients with TM.…”