Autologous HSCT Induce a Sustained Inhibition of New MRI Lesions in Severe Refractory Multiple Sclerosis.

Long Term Results of a Prospective Multicenter Trial

Riccardo Saccardi1*, Massimo Filippi2*, Maria Pia Sormani3*, Massimo Di Gioia4*, Alberto Bosi4, Paolo Di Bartolomeo, MD5, Amedea Donelli6*, Francesca Gualandi7*, Angelo Guerrasio8*, Giorgio La Nasa9*, Pietro Maggi10*, Alberto Marmont11*, Federico Papineschi12*, Luisa Vuolo13*, Maria Annunziata Rocca2* and Gian Luigi Mancardi14*

Number: 1221 ID: 22002

1BMT

Unit, Department of Hematology, Policlinico di Careggi, Firenze, Italy; 2Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, Milan, Italy; 3Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy, Italy; 4Hematology, Universita' degli Studi di Firenze, Florence, Italy; 5Dipartimento Ematologia, Centro Trapianti Midollo Osseo, Pescara, Italy; 6Division of Hematology, Modena University Hospital, Modena, Italy; 7Department of Hematology II, San Martino's Hospital, Genova, Italy; 8Internal Medicine II, San Luigi Gonzaga Hospital, Orbassano, Italy; 9Cagliari University; 10Hematology, Universit degli Studi di Firenze, Florence, Italy; 11Department of Haematology II, Ospedale San Martino, Genova, Italy; 12Division of Haematology - Department of Oncology, Transplants and Advances in Medicine, University of Pisa, Pisa, Italy; 13Dipartimento di Neuroscienze, Oftalmologia e Genetica, Universit degli Studi di Genova, Genova, Italy; 14Clinica Neurologica Universit, Ospedale San Martino, Genova, Italy

A subset of Multiple Sclerosis (MS) patients shows a clinical trend to a fast deterioration of disability despite the use of multiple lines 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 due to toxicity. 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 [1]. We report here the long term follow-up of a prospective phase II multicenter trial of the Italian GITMO-Neuro cooperative network.

Total number of lesions

BACKGROUND

90 80 70 60 50 40 30 20 10 Month -1 Month +1 Months +12 Months +24 Long-term FU

HSCT

RESULTS
All patients showed a sustained engraftment with modest early side effects, as previously reported [2]. 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 (0.5 points of EDSS in 4 patients, 1.0 point of EDSS in 2 patients, and 1.5 points of EDSS in 3 patients)sat a median of 30 months (16 66) after transplant, while the others are either stable (7) or improved (5), as compared with baseline (Fig3-4.). No patients received any immunosuppressive treatment after HSCT. At MRI examination, performed on 18 patients with a complete follow-up, total lesion load assessed by T2 and T1 sequences remained stable through the follow-up, and only 5 new T2 lesions appeared after HSCT (Fig5.). No Gd enhancing activity was ever observed after transplantation in the examined cases (Fig6.). Brain atrophy progression was higher in the first 2 years after transplantation and then decreased significantly in the following years

MATERIALS AND METHODS

Fig5. New T2 Lesions: Long-term follow-up MRI analysis has been perfromed with the same protocol as the previously exams. Only 4 new T2 lesions were observed from months +24 and Long term MRI exams, on 18 patients
16 16

Median lesions/patients

14 14

12 12

10 10

88 66 44 22 00
screening Screening

HSCT

Fig1. Mobilization and Conditioning Regimens

Progression-free Survival

-1mese Cy +30 giorni +2mesi +5mesi +12mesi +24mesi -1 Month 30 Months +5 Months +12 Months +24 Months follow-up Long-term days after +2 Follow-up mobilization

21 MS patients were enrolled between 1999 and 2004 in a prospective trial, aimed to monitor both clinical outcome and MRI imaging (Tab1.). PBSC were mobilized with Cyclophosphamide (4g/m2 ) and Filgrastim; patients were conditioned with BEAM plus rabbit ATG (Thymoglobulin, Genzyme) and infused with unmanipulated graft (Fig1.).

Fig6. Gd+ enhancing lesions: No MRI activity has been evaluated with MRI exams from +24 months after HSCT and the last visit at Long-term Follow-up

57,1%

CONCLUSIONS
Fig3. Progression free survival: progression is considered a worsening of the EDSS at least 1.0 points if baseline EDSS was <5.5 (confirmed at 6 months), or a worsening of the EDSS at least 0.5 points if baseline EDSS was 5.5 (confirmed at 6 months).

GITMO.Trial

Time from HSCT (Months)

Fig2. Study Design

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. Brain atrophy was shown to decrease at 2 years from HSCT [3]. The assessment at the last follow-up is currently in progress. To our knowledge, this is the foirst rteport of long-term MRI assessment of new T2 lesions in a prospective trial. 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. In particular we observed an overall stabilization effect on the disease progression that must be further investigated, in particular if we consider that, despite in presence of a positive MRI (with triple dose of Gadolinium) at screening, these patients were in the progressive phase of the disease where standard immunosuppresive therapy have poor impact.

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 as per study design (Fig2.). 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

REFERENCEs
1. Mancardi G, Saccardi R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol 2008;7(7):626-36. 2. 2. Saccardi R, Mancardi GL, Solari A, et al. Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life. Blood 2005;105(6):2601-7. 3. 3.Roccatagliata L, Rocca M, Valsasina P, Bonzano L, Sormani M, Saccardi R, Mancardi G, Filippi M. The long-term effect of AHSCT on MRI measures of MS evolution: a five-year follow-up study. Multiple sclerosis (Houndmills, Basingstoke, England) 2007;13(8):1068-70.

Fig4. Boxplot EDSS: the boxplot graphic rapresentation show a sustantial stabilization of the progression fo the disability at long term follow-up, in patients that failed to respond to conventional treatment and were in the progressive phase of the disease.