Autologous HSCT Induce a Sustained Inhibition of New MRI Lesions in Severe Refractory Multiple Sclerosis. Long Term Results of a Prospective Multicenter Trial.

A subset of Multiple Sclerosis (MS) patients shows a clinical trend to a fast deterioration of disability despite the use of approved drugs. New immunosuppressive agents are currently employed only in the early phase of the disease but in almost 10% of patients they either do not show any clinical/ radiological improvement or have to be halted for different reasons. Autologous HSCT has been reported as a promising approach for MS patients unresponsive to the available therapies but long term clinical and laboratory follow-up with a stringent MRI monitoring are not yet available. We report here the long term follow-up of a prospective phase II multicenter trial of the Italian GITMO-Neuro cooperative network.

21 MS patients (4 Relapsing Remitting and 17 Secondary Progressive) were enrolled between 1999 and 2004 in a prospective trial, aimed to monitor both clinical outcome and MRI imaging. Patients were shown to be refractory to conventional treatments, had a EDSS between 5.0 and 6.5 and at least 1 Gadolinium (Gd) enhancing area in brain MRI. PBSC were mobilized with Cyclophosphamide (4g/m² ) and Filgrastim; patients were conditioned with BEAM plus rabbit ATG (Thymoglobulin®, Genzyme) and infused with unmanipulated graft. The effect of HSCT was evaluated with serial monthly Gd-enhanced brain MRI for a pretreatment period of 3 months and compared with serial monthly Gd-enhanced MRI imaging for the following 6 months. Subsequently, MRI scans were carried out at, +9, +12, +18 + 24 and at the last follow-up. Clinical outcome was evaluated by both EDSS assessment and number of clinical relapses after the transplant. The same MRI scanning protocol was used at each neuroradiological examination: T1 and T2 total lesion load, new T2 lesions, new hypointense lesions, Gd enhancing activity and progression of brain atrophy were evaluated.

All patients showed a sustained engraftment with modest early side effects, as previously reported (Saccardi R. et al. Blood 2005 105:2601-07). At a median follow up of 7 years (range 4-10 years) no late effects were reported. Two patients had a clinical relapse 5 years after the HSCT, spontaneously recovered. Nine patients showed a clinical progression at a median of 30 months (16 – 66) after transplant, while the others are either stable (7) or improved (5), as compared with baseline. No patients received any immunosuppressive treatment after HSCT. At MRI examination total lesion load assessed by T2 and T1 sequences remained stable through the follow-up, and only 5 new T2 lesions appeared after HSCT. No Gd enhancing activity was ever observed after transplantation in the examined cases. Brain atrophy progression was higher in the first 2 years after transplantation and then decreased significantly in the following years

The clinical and MRI results of this prospective study are extremely positive, considering that the majority of cases remained stable at a median of 7 years after transplantation. MRI activity, as evaluated with Gd enhancing areas and the appearance of new lesions, was absent or negligible. Also brain atrophy, rapidly progressing early after the transplant probably due to the suppression of the inflammation, was thereafter shown to be in the range of MS patients. The duration of the follow-up and the stringent MRI methodology provide an evidence of the efficacy of this procedure in this subset of aggressive MS patients.

No relevant conflicts of interest to declare.