Autologous haematopoietic stem cell transplantation versus low-dose immunosuppression in secondary-progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Effectiveness of autologous haematopoietic stem cell transplantation (AHSCT) in relapsing-remitting multiple sclerosis (MS) is well known, but in secondary-progressive (SP)-MS it is still controversial. Therefore, AHSCT activity was evaluated in SP-MS using low-dose immunosuppression with cyclophosphamide (Cy) as a comparative treatment. METHODS: In this retrospective monocentric 1:2 matched study, SP-MS patients were treated with intermediate-intensity AHSCT (cases) or intravenous pulses of Cy (controls) at a single academic centre in Florence. Controls were selected according to baseline characteristics adopting cardinality matching after trimming on the estimated propensity score. Kaplan-Meier and Cox analyses were used to estimate survival free from relapses (R-FS), survival free from disability progression (P-FS), and no evidence of disease activity 2 (NEDA-2). RESULTS: A total of 93 SP-MS patients were included: 31 AHSCT, 62 Cy. Mean follow-up was 99 months in the AHSCT group and 91 months in the Cy group. R-FS was higher in AHSCT compared to Cy patients: at Year 5, 100% versus 52%, respectively (p < 0.0001). P-FS did not differ between the groups (at Year 5: 70% in AHSCT and 81% in Cy, p = 0.572), nor did NEDA-2 (p = 0.379). A sensitivity analysis including only the 31 "best-matched" controls confirmed these results. Three neoplasms (2 Cy, 1 AHSCT) and two fatalities (2 Cy) occurred. CONCLUSIONS: This study provides Class III evidence, in SP-MS, on the superior effectiveness of AHSCT compared to Cy on relapse activity, without differences on disability accrual. Although the suppression of relapses was observed in the AHSCT group only, AHSCT did not show advantages over Cy on disability, suggesting that in SP-MS disability progression becomes based more on noninflammatory neurodegeneration than on inflammation.

Incidence of malignant neoplasms and mortality in people affected by multiple sclerosis in the epoch of disease-modifying treatments: A population-based study on Tuscan residents.

BACKGROUND: Conflicting data are currently available on the risk of malignancies in people affected by multiple sclerosis (pwMS), and the potential relative contribution to this risk of disease-modifying therapies (DMTs) is still debated. Moreover, data on the long-term prognosis of pwMS mostly derive from natural history studies and updated observations during the treatment era are lacking. METHODS: Incidence of cancer and mortality were analysed in a pwMS cohort of residents of Tuscany over a 17-year period of observation during the treatment era and compared with the rates observed in a 1:10 sex- and age-matched control population resident in the same geographical area. RESULTS: Six-hundred and sixty-one pwMS were included; median age 43 years (range 19-80); 87% affected by relapsing-remitting MS. Sixty-eight percent of the cases were exposed to DMTs over the study period. Age and sex standardized incidence of malignancy did not differ between the groups: 3.9 × 1000 (95% confidence interval, CI, 3.75-4.15) person-years and 4.1 × 1000 (95% CI 3.76-4.42) person-years in the MS and control cohorts, respectively. The most frequent cancers reported in pwMS were breast, gastrointestinal and gynaecological cancers. Standardized mortality rates were 2.0 × 1000 person-years (95% CI 1.58-2.37) and 2.4 × 1000 (95% CI 2.03-2.78) person-years in the MS and control cohorts, respectively, and did not differ between groups, also after excluding traumatic cause-of-death (1.6 vs 1.7). CONCLUSIONS: The incidence of cancer and mortality did not differ between pwMS and the general population residing in the same geographical area, suggesting that life expectancy of pwMS has improved over the treatment era.

Impact of autologous haematopoietic stem cell transplantation on disability and brain atrophy in secondary progressive multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (aHSCT) is a valuable option in aggressive relapsing-remitting multiple sclerosis (MS), but its efficacy in secondary progressive (SP)-MS is still controversial. OBJECTIVE: Assessing efficacy of aHSCT in SP-MS by clinical-radiological outcomes. METHODS: Open-label monocentric retrospective study enrolling consecutive SP-MS patients treated with BEAM-aHSCT in the period 1999-2016. RESULTS: In total, 26 SP-MS patients with moderate-severe disability were included. Progression-free survival (PFS) at years 5 and 10 after aHSCT were, respectively, 42% and 30%. Out of 16 patients who worsened, only 6 patients (23% overall) maintained continuous disability accrual (CDA), whereas 10 patients stabilized following one single-step Expanded Disability Status Scale (EDSS) worsening. CDA-free survival was 74% at 5-10 years. No relapses or magnetic resonance imaging (MRI) activity were reported, thus no evidence of disease activity (NEDA)-3 corresponded to PFS. Annualized rate of brain atrophy (AR-BVL) normalized after 1 year in 55% of the cases analysed (12/22). CONCLUSION: BEAM-aHSCT halted CDA and normalized AR-BVL in most of the treated patients, inducing long-term remission of inflammatory activity at a median follow-up of 99 months (range 27-222). These data suggest that CDA might still be mainly driven by inflammation in a subgroup of SP-MS and could therefore be reversed by treatments. CDA should be analysed independently from any isolated disability worsening.

Sustained disease remission after discontinuation of disease modifying treatments in relapsing-remitting multiple sclerosis.

BACKGROUND: The natural history of multiple sclerosis (MS) following discontinuation of a first-line disease-modifying treatment (DMT) in relapsing-remitting (RR-) MS patients is controversial, as few data are available on the risk of disease reactivation. This study aims to investigate the disease course after DMT discontinuation in selected RR-MS patients, exploring potential predictive factors of disease reactivation. METHODS: RR-MS patients, aged 18-65, who had discontinued a first-line DMT were selected from 1107 clinical records. Relapses, disability worsening and new brain lesions, before and after DMT interruption, were retrospectively evaluated. Potentially predictive baseline characteristics of disease reactivation were also analysed. RESULTS: N= 60 patients were included, median age and treatment duration were 47.8 (22.1-64.3) and 7.2 (0.5-17.8) years respectively. Median clinical follow-up after discontinuation was 4.6 (0.5-16.6) years. No disease rebound occurred. Mean annualized disease activity and relapse rate after discontinuation were both lower than during treatment(0.10±0.05 vs 0.15 ±0.05; p=0.017). A NEDA-3 period on treatment ≥5.5 years was associated with a low rate (7.7%) and a low risk of new disease activity (aHR 0.16, CI 0.03-0.78, p=0.024; Cox regression model multivariate analysis). The patients with NEDA-3 period threshold above 5.5 years showed a higher probability of surviving to disease reactivation than others (p=0.014). CONCLUSION: In most of the MS patients who showed a long NEDA-3 period while on treatment remission of disease activity persists following first-line DMT discontinuation, suggesting that prolonged suppression of disease activity on treatment can determine long term sustained remission of the disease also in absence of treatment.

Disease reactivation following fingolimod withdrawal in multiple sclerosis: Two case reports.

BACKGROUND: Severe multiple sclerosis reactivation following second line treatment withdrawal, defined "rebound syndrome", is becoming a prominent issue to consider when deciding to discontinue a treatment. In particular disease recurrence after cessation of fingolimod is actually poorly characterized as to date, only case reports and small case series have been described. CASE PRESENTATION: We herewith describe 2 cases of severe disease reactivation associated to a high number of brain gadolinium enhancing lesions at magnetic resonance imaging (MRI) despite high dose steroid treatment, observed a few weeks after cessation of fingolimod administration, causing a substantial and persistent worsening of patient disability that required long term hospitalization. The severity of the neurological symptom worsening and of the brain lesion largely exceeded the disease activity observed during treatment. CONCLUSIONS: Our patients developed a rebound syndrome after ceasing fingolimod treatment, defined as the development of severe neurological symptoms and multiple new or enhancing lesions exceeding previous activity. Further analysis are needed to identify patients at greatest risk of a rebound syndrome.