Fludarabine and treosulfan: A novel modified myeloablative regimen for allogeneic hematopoietic stem-cell transplantation with effective antileukemia activity in patients with acute myeloid leukemia and myelodysplastic syndromes

Abstract

Allogeneic stem-cell transplantation (SCT) is potentially curative treatment for AML and MDS. New conditioning regimens are continuously explored trying to reduce toxicity while maintaining antileukemia effect. Treosulfan is an alkylating agent with in vitro cytotoxicity against leukemia as well as myeloablative and immunosuppressive properties when used in escalated doses. We explored a regimen of fludarabine (30 mg/m(2) x 5) and treosulfan (12 gr/m(2) x 3) in 24 patients, median age 55 years (range, 30-69), with AML (n = 19) or MDS (n = 5), not eligible for standard myeloablation. Donors were HLA-matched siblings (n = 11) or matched-unrelated (n = 13). Twenty-one patients engrafted within a median of 15 days. Extramedullary toxicity was relatively limited. The incidence of acute and chronic GVHD was 15% and 47%, respectively. With median follow-up of 19 months (range, 8 - 34), 16 patients are alive and 8 died (relapse-2, treatment-related-6). Two-year disease-free survival rate was 60% (95% CI, 39-81). The cumulative incidence of relapse was only 15% (95% CI, 5 - 44) while nonrelapse mortality rate was 25% (95% CI, 13-50). The fludarabine/treosulfan regimen can be considered a fully intensive, modified myeloablative regimen with effective antileukemia activity and acceptable toxicity in patients with AML/MDS not eligible for standard myeloablation, and merits further study in larger scale studies.

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

“…FT was associated with rapid achievement of full donor chimerism, similar to FB4 and to MAC regimens, while the kinetics of engraftment of FB2 is more consistent with RIC/ NMA. Prior studies have documented a safe toxicity profile of FT. 8,16,22,23 In this study, severe mucositis was less often seen after FT, but the incidence of other organ toxicities was similar after the various regimens. The day of onset of neutropenia was significantly earlier after FT, consistent with the activity of treosulfan against both committed and non-committed stem cells, while BU spares committed stem cells.…”

“…Some of the patients were included in previous publications. 3,8 Although enrolment years were overlapping, FT recipients were treated more recently (Table 1). Patients with AML were eligible for allo-SCT if they had AML in first CR at high risk for disease relapse owing to poor-risk cytogenetic or molecular characteristics (internal tandem duplication of fms-like tyrosine kinase receptor-3) according to the European LeukemiaNet criteria, 9 a high WBC count at presentation, no response to the first induction chemotherapy course and secondary leukemia or if they were beyond first CR.…”

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike

“…Secondary failure of engraftment was only rarely documented. 43 In our study that included patients with AML and Treosulfan-based conditioning I Danylesko et al MDS, 41 the neutropenia started earlier than seen in RIC studies. Neutropenia was first detected on median day 0, compared with median day þ 6 after RIC consisting of fludarabine and BU, and more similar to the kinetics of MAC.…”

“…23,40,43,44,46 Several studies included more homogeneous diseases, but were still based on small number of patients. 41,42,45,47 The main findings of currently available studies are summarized in Table 2.…”

“…daily over 30 min from days À6 to À2). [39][40][41][42][43][44][45][46] For patients with unrelated donors, antithymocyte globulin (for example, ATG Fresenius, Fresenius Biotech, Munich, Germany (5-10 mg/kg)) was given i.v. daily from days À3 to À1.…”