Treosulfan-Based Preparative Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Children with Increased Risk of Conventional Regimen Toxicity.

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/m 2 , n=22; 3x12 g/m 2 , n=19; 3x14 g/m 2 , 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 (1.7x10 6 /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/m 2 i.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.