OBJECTIVE : To study the safety and efficacy of treosulfan, a cytotoxic alkylating agent, in patients with active secondary progressive multiple sclerosis. BACKGROUND : Treosulfan (L-threitol-1,4-bis(methanesulfonate)) is a bifunctional alkylating agent with a favorable profile of side effects, approved for the treatment of ovarian cancer. Treosulfan has previously been shown to reduce the severity of experimental allergic encephalomyelitis under pre-therapeutic and therapeutic conditions. In human peripheral blood mononuclear cells, treosulfan reduces proliferative capacity and increases apoptosis. STUDY DESIGN : This is a nonrandomized, open label study conducted in two centers. Eleven patients with active secondary progressive MS that failed to or did not qualify for approved disease modifying drugs were treated with treosulfan for 1 year. Patients received intravenous infusions of 7 g/m(2) 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 MRI was performed every 3 months, EDSS and MSFC as well as physical examination were assessed at each clinical visit. 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 drug 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 signifi- cantly by 1.5 (range -3 to 0), p <0.016, compared to prestudy. Therapy with treosulfan lead to a clear reduction of MRI activity as revealed by a reduced number of Gd + enhancing lesions on T1 weighted images. The mean number and volume of T2 lesions remained unchanged over 1 year. Four out of 9 patients under treosulfan showed no detectable disease activity (no Gd enhancing lesions, no new or newly enlarging T2 lesions). CONCLUSIONS : Application of treosulfan in MS was safe and well tolerated. Further studies are warranted to evaluate the efficacy of this treatment in secondary progressive MS.
