Treosulfan-Based Preparative Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Children with Increased Risk of Conventional Regimen Toxicity.
Authors: Wachowiak Jacek , Chybicka Alicja , Kowalczyk Jerzy , Grund Grzegorz , Boruczkowski Dariusz , Gorczynska Ewa , Wojcik Beata , Leda Michal , Turkiewicz Dominik , Drabko Katarzyna 
Published: October 2019

Abstract
It was investigated whether in children demonstrating high risk of toxicity related to conventional preparative regimens (prep-reg) for allo-HSCT, the prep-reg based on Treosulfan (TREO) (Feit, Rastrup-Andersen, 1970) enables to avoid severe toxic complications without increased incidence of graft failure and/or relapse. From July 2000 to April 2005 the TREO-based prep-reg was used prior to allo-HSCT in 43 children with increased risk of severe Busulfan- and FTBI-based regimens related toxicity (RRT) and/or non-compliance. In 37 patients (pts) allo-HSCT was performed for, usually advanced, hematological malignancy, incl. 19 pts (1–17 yrs, med. 9) transplanted from MSD for ALL (n=8), AML (n=7), LCH (n=2), MDS (n=1) and NHL (n=1), and 18 pts (0.5–17 yrs, med. 9.5) from MUD for AML (n=7), ALL (n=4), CMML (n=3), NHL (n=2) and CML (n=2). Six pts (0.5–12 yrs, med. 6) underwent HSCT for congenital disorder, i.e. 5 from MSD for ALD (n=2), WAS (n=2) and B-DA (n=1), and one from MUD for osteopetrosis. Total of 24 pts were transplanted from MSD and 19 from MUD. TREO (3x10 g/m2, n=22; 3x12 g/m2, n=19; 3x14 g/m2, n=2) was given i.v. in various combination with FLUDA, CY, MEL or VP-16 acc. to diagnosis, risk factors of RRT and/or regimen used for previous HSCT. Prior MUD-HSCT and all pts with congenital disorders received ATG (n=18) or Campath (n=3). RRT was graded acc. to Bearman (1988). In 21 out of 43 pts (incl. all 6 with congenital diseases) no features of RRT occured, I° in 13, II° in 5, and III° in 4 (mucositis). Engraftment was achieved in all pts, except one transplanted from MUD for CML with low dose of CD34 cell (1.7x106/kg). Acute GvHD II–III° occurred in 9/24 pts after MSD-HSCT and in 10/19 after MUD-HSCT, chronic GvHD in 4/24 post MSD-HSCT and 1/19 after MUD-HSCT. Chimerism was evaluated in 22/24 pts after MSD-HSCT and in 18/19 post MUD-HSCT. Respectively, complete donor chimerism was observed in 17/22 and 16/18 pts, mixed in 5/22 and 1/18, and autologous recovery in 1/18 after MUD-HSCT. Non-relapse deaths occurred in 6 out of 37 pts with malignancy, incl. one 40 mo. post MSD-HSCT (pulmonary aspergillosis, cGvHD), and 5 after MUD-HSCT (abdominal aorta thrombosis day+59, LPD day+63, BKV infection day+66; intracranial bleeding day+138). The 1-year non-relapse mortality was 13,5%. Relapse was diagnosed in 8/19 pts post MSD-HSCT (4xAML, 4xALL) and in 1/18 after MUD-HSCT (sAML). Out of 24 pts transplanted from MSD, 15 are alive, i.e. 10/19 with malignant disease in CCR (med. 27, 16–50 mo.) and 5/5 with congenital disorder (med. 21, 6–58 mo.). After MUD-HSCT, 12/18 pts with malignancy are alive in CCR (med. 19, 7–42 mo.) and a child with osteopetrosis (4 mo.). At 3 years from HSCT in 19 pts with malignancy transplanted from MSD the progression-free survival (PFS) was 46% and overall survival (OS) 49%, while in 18 transplanted from MUD 82% and 68%. The PFS and OS estimated for 6 pts with congenital disorders at 4 years after HSCT was 67% and 100%. Conclusions: In children with high risk of conventional regimen related toxicity the prep-reg for allo-HSCT based on TREO given at the dose of 3 x 10–12 g/m2i.v. demonstrates almost exclusively mucosal toxicity, along with sufficient myeloablative and immunosuppressive effects. Its anti-leukemic effect is at least comparable with that one of Busulfan-based regimens.