A phase III, randomized controlled trial «Burt RK, Balabanov R, Burman J, ym. Effect of Nonm...»1 (MIST) compared the effect of nonmyeloablative hematopoietic stem cell transplantation (HSCT) vs disease-modifying therapy (DMT) on disease progression of relapsing-remitting multiple sclerosis (MS). The study included 110 patients (73 [66%] women; mean age 36 [SD, 8.6] years). Inclusion criteria were relapsing-remitting MS according to McDonald criteria, age 18 to 55 years, 2 or more clinical relapses or 1 relapse and MRI gadolinium-enhancing lesion(s) at a separate time within the previous 12 months despite receiving treatment with DMT, and an Expanded Disability Status Scale (EDSS) score between 2.0 and 6.0. Patients were recruited from the US, UK, Brazil and Sweden. Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55). DMTs used as the comparator for HSCT were for 21 patients natalizumab, 14 dimethyl fumarate, 14 fingolimod, 9 glatiramer acetate, 7 interferon beta-1a, 6 mitoxantrone, and 1 teriflunomide. The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more on 2 evaluations 6 months apart. 103 patients remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. For the HSCT group, the proportion of patients with disease progression was 1.92% (95% CI, 0.27%-12.9%) at 1 year and 2 years, 5.19% (95% CI, 1.26%-20.1%) at 3 years, and 9.71% (95% CI, 3.0%-28.8%) at 4 and 5 years. For the DMT group, the proportion of patients with disease progression was 24.5% (95% CI, 14.7%-39.1%) at 1 year, 54.5% (95% CI, 40.7%-69.4%) at 2 years, 62.5% (95% CI, 48.3%-76.7%) at 3 years, 71.2% (95% CI, 56.8%-84.2%) at 4 years, and 75.3% (95% CI, 60.4%-87.8%) at 5 years. There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities.
A phase II, randomized, controlled trial «Mancardi GL, Sormani MP, Gualandi F, ym. Autologou...»2 assessed the effect of intense immunosuppression followed by autologous hematopoietic stem cells transplantation (AHSCT) in MS. The patients with secondary progressive or relapsing-remitting MS, with a documented increase on EDSS during the last year in spite of conventional therapy, and presence of at least one gadolinium enhancing lesion (GEL) were included. Patients were randomized to receive intense immunosuppression followed by AHSCT or intravenous mitoxantrone (MTX) 20 mg every month for 6 months. The primary endpoint was the cumulative number of new T2 lesions in the 4 years follow-up. Secondary endpoints were the cumulative number of GELs, relapse rate and disability progression. Adverse events were also reported. Intention to treat analysis was performed according to the last observation carried forward. Twenty-one patients were randomized (AHSCT n=9, MTX n=12) and 17 had postbaseline evaluable MRI scans. Mean age was 35.5 years and median EDSS 6 (range 5.5-6.5). The mean number of new T2 lesions was in the AHSCT group 2.75 (range 0-8) and in MTX group 12.75 (2-34), rate ratio 0.21 (95 % CI 0.10-0.48, p = 0.00016). The annualized relapse rate was 0.19 for AHSCT and 0.6 for MTX (RR 0.36, 95 % CI 0.15-0.88, p=0.026). No difference in the EDSS changes was observed between the groups.
A randomized, placebo-controlled cross-over phase II study «Llufriu S, Sepúlveda M, Blanco Y, ym. Randomized p...»3 investigated the safety and efficacy of mesenchymal stem cells (MSCs) in MS. The patients unresponsive to conventional therapy, defined by at least 1 relapse and/or at least one GEL on MRI in past 12 months, aged 18 to 50 years, disease duration 2 to 10 years and EDSS 3.0-6.5 were included. Exclusion criteria were active or chronic infection, treatment with any immunosuppressive therapy within the previous 3 months or interferon-beta, glatiramer acetate or corticosteroids within 30 days prior to randomization. Patients were randomized to receive intravenous (IV) 1-2×10(6) bone-marrow-derived-MSCs/kg or placebo. After 6 months, the treatment was reversed and patients were followed-up for another 6 months. The primary endpoints were safety and efficacy in terms of cumulative number of GELs on MRI between groups (6 months) and the reduction in the mean number of GELs (at the end). Secondary endpoints were clinical outcomes (relapses and disability by EDSS and MS Functional Composite), and several brain MRI and optical coherence tomography measures. At baseline, 9 patients were randomized to receive MSCs (n=5) or placebo (n=4). At baseline median age was 41 years (range 23-48), median disease duration 9 years (4.31-10.00), median EDSS 3.5 (3.0-6.0) and median number of GELs 0 (0-22). One patient on placebo withdrew after having 3 relapses in the first 5 months. No serious adverse events were identified. At 6 months, mean cumulative number of GELs was 3.1 (95 % CI 1.1-8.8) for patients treated with MSCs and 12.3 (4.4-34.5) for placebo group (p=0.064). At the end of study mean change in GELs during the period of MSCs was -2.8±5.9 and during the placebo period 3±5.4 (p=0.075). No significant treatment differences were detected in the secondary endpoints.
Comment: There are more open-label studies. It seems that stem cell transplantation is associated with few serious or unexpected adverse events «Nash RA, Hutton GJ, Racke MK, ym. High-dose immuno...»4, «Cohen JA, Imrey PB, Planchon SM, ym. Pilot trial o...»5, «Atkins HL, Bowman M, Allan D, ym. Immunoablation a...»6, of which the most common are infections. A Swedish MS-register-based observational study reported febrile neutropenia for 28/69 patients (41%) during the first 100 days «Zhukovsky C, Sandgren S, Silfverberg T, ym. Autolo...»7, and another Swedish register study «Alping P, Burman J, Lycke J, ym. Safety of Alemtuz...»8 on 139 AHSCT patients confirmed this also over 6 months from therapy start (incidence rate for infections 108/1000 person-years (95% CI 75–150). A cohort study «Muraro PA, Pasquini M, Atkins HL, ym. Long-term Ou...»9 evaluated the long-term (median follow-up 6.6 years) outcomes in patients who underwent AHSCT for the treatment of MS and eight deaths (2.8 %) were reported within 100 days from AHSCT and were considered AHSCT-related. A retrospective Italian study «Boffa G, Massacesi L, Inglese M, ym. Long-Term Cli...»10 on 210 patients reported that disability worsening–free survival was 85.5% in RRMS (95% CI 76.9%–94.1%) at 5 years and 71.3% (57.8%–84.8%) at 10 years, and in progressive MS, 71.0% (59.4%–82.6%) and 57.2% (41.8%–72.7%) at 5 and 10 years, respectively; No deaths occurred in patients transplanted after 2007.