Allo-SCT for AML and MDS with treosulfan compared with BU-based regimens: reduced toxicity vs reduced intensity

Abstract

Allo-SCT with reduced-intensity conditioning (RIC) results in lower non-relapse mortality (NRM), but higher relapse rate than myeloablative conditioning (MAC) in AML/myelodysplastic syndromes (MDS). Novel regimens with intensive anti-leukemic activity, but with limited toxicity will be of benefit. In all, 85 patients with AML/MDS, not eligible for MAC, were given fludarabine-treosulfan conditioning (FT). Outcomes were compared with those in patients given fludarabine-BU RIC (FB2, n ¼ 106) or reduced-toxicity (RTC) conditioning (FB4, fludarabine and myeloablative BU dose, n ¼ 85). The 5-year NRM was 29%, 20% and 18% after FT, FB2 and FB4, respectively (P ¼ NS). Multivariate analysis (MVA) identified comorbidity score (HCT-CI) 42 and advanced disease as adverse factors with no independent impact of regimen. The 5-year relapse rate was 36%, 47% and 40%, respectively (P ¼ 0.17). MVA identified advanced disease as the major adverse factor, while FT had significantly lower relapse rate (hazard ratio 0.6, P ¼ 0.03). The 5-year survival (OS) was 37% with advanced disease. HCT-CI 42 and age X50 were found as adverse factors. The 5-year OS was 46%, 44% and 50% after FT, FB2 and FB4 in early-intermediate-stage disease (P ¼ NS) and 33%, 9% and 28% in advanced disease, respectively (P ¼ 0.02). FT is an RTC regimen with intensive anti-leukemia effect in MAC non-eligible patients.

Fludarabine and treosulfan compared with other reduced-intensity conditioning regimens for allogeneic stem cell transplantation in patients with lymphoid malignancies

“…39 However, chronic GvHD rates are similar after FT and other RIC or MAC regimens. 29,40 Similar to other studies advanced age, comorbidities, unrelated donor and chemo-refractory disease were also associated with higher NRM.…”

“…We have compared FT with busulfan based RIC or MAC regimens in patients with AML and myelodysplastic syndromes. 29 FT was associated with similar NRM as RIC, but controlled leukemia better, resulting in better outcome in patients with advanced disease at SCT. There are only limited data on the use of FT in lymphoid malignancies.…”

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).…”

“…Probably, TREO provides lower organ toxicity than busulfan, especially hepato-, pulmo-, and neurotoxicity. One hypothesis that needs experimental verification assumes that because of lower lipophilicity of TREO compared with busulfan, the former achieves lower concentrations in those key organs and, consequently, is less toxic (Główka et al, 2010;Danylesko et al, 2012;Shimoni et al, 2012). The underlying mechanism of potentially low neurotoxicity of TREO appears particularly important for infants, as maturity of their blood-brain barrier (BBB) is still unknown (Saunders et al, 2012).…”

“…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.…”