Haematopoetic stem cells in MSSaturday, October 13, 2007, 11:46 - 11:58
Treatment of active secondary progressive Multiple sclerosis with treosulfanH. Wiendl, B.C. Kieseier, R. Weissert, H.-P. Hartung, A. Melms, W. Kueker, M. Weller (Wurzburg, Dusseldorf, Tubingen, D; Oxford, GB)
Objective: Safety and efficacy of treosulfan in patients with active secondary progressive multiple sclerosis (SP-MS).
Background: Treosulfan (L-threitol-1,4-bis[methane sulfonate]) is the prodrug of a bifunctional alkylating agent with a favourable profile of side effects, approved for the treatment of ovarian cancer. Immunosuppressive characteristics and pro-apoptotic capacity of treosulfan has been shown on a variety of immune cells. Beneficial effects have been demonstrated in experimental autoimmune encephalomyelitis (EAE) under pre-therapeutic and therapeutic conditions.
Study design: In a nonrandomized, open label study eleven patients with active SP-MS who received approved disease modifying drugs that failed to take effect or did not qualify for those drugs were treated with treosulfan for 1 year. Patients received intravenous infusions of 7 g/m2 every 4 weeks for 3 months (cycles 1-4, induction phase) with a predefined one-step dose escalation, thereafter every 3 months for the following 9 months (cyles 5-7, maintainance phase). Cranial MRIs were performed every 3 months, EDSS and MSFC as well as physical examinations were assessed at each clinical visit. Immunocompetent cells from peripheral blood were analyzed in parallel.
Results: Treatment with treosulfan was safe and well tolerated. Nine of 11 patients remained on study drug over the complete treatment period and showed clinical stabilisation or improvement as determined by EDSS and MSFC. Two patients discontinued study participation because of leukocytopenia and withdrawal of consent, respectively. No clinical relapses were observed during the treatment period. Thus, the median number of relapses per year was reduced significantly by 1.5 (range -3 to 0, p<0.016) compared to pre-study. The mean number and volume of T2 lesions as well as T1 lesions did not change significantly over 1 year. Five out of 10 patients under treosulfan showed no newly active lesions, e.g. no Gd enhancing lesions, no new or newly enlarging T2 lesions.
Conclusions: Clinical as well as MRI measures provide initial evidence of efficacy of Treosulfan in active SP-MS. Overall the treatment was safe and well tolerated. Data of this proof-of-concept study support the realisation of a randomised, placebo-controlled three-arm parallel-group, double-blind, multicentre dose-ranging study in secondary progressive and progressive relapsing multiple sclerosis.
Sponsored by: medac GmbH, Wedel, Germany