The purpose of the study was to determine the long-term safety and effectiveness of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic cell transplantation (AHCT) in ...advanced multiple sclerosis (MS). TBI, CY and antithymocyte globulin were followed by transplantation of autologous, CD34-selected PBSCs. Neurological examinations, brain magnetic resonance imaging and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. Patients (n=26, mean Expanded Disability Status Scale (EDSS)=7.0, 17 secondary progressive, 8 primary progressive, 1 relapsing/remitting) were followed for a median of 48 months after HDIT followed by AHCT. The 72-month probability of worsening ≥1.0 EDSS point was 0.52 (95% confidence interval, 0.30-0.75). Five patients had an EDSS at baseline of ≤6.0; four of them had not failed treatment at last study visit. OCB in CSF persisted with minor changes in the banding pattern. Four new or enhancing lesions were seen on MRI, all within 13 months of treatment. In this population with high baseline EDSS, a significant proportion of patients with advanced MS remained stable for as long as 7 years after transplant. Non-inflammatory events may have contributed to neurological worsening after treatment. HDIT/AHCT may be more effective in patients with less advanced relapsing/remitting MS.
The potent immunostimulatory cytokine interleukin-2 (IL-2) has been extensively investigated for its potential to induce anti-tumor immunity in a number of tumor models. Only recently the complex ...interplay of mutually suppressive or supportive cytokines of the IL-2-induced network of cytokines has been better characterized. The aim of this study was to assess which of these in vitro findings are reproducible in vivo in recipients of stem cell transplants (SCT), since in these patients long- lasting impairments in cytokine inducibility have been described. We have therefore studied the kinetics of putative modulators and mediators of IL-2-induced immune activation, namely IL-1beta, IL-4, IL-5, IL-10, IL-12, soluble Fas ligand (sFasL), and GM-CSF during IL-2 therapy. All patients were children or adolescents suffering from solid tumors with poor prognosis who received three 5-day courses of high-dose intravenous IL-2 as an adjuvant to their radio-chemotherapy and autologous SCT. While IL-1beta, IL-4 and IL-12 were not, and sFasL was only mildly affected by the IL-2 therapy, we observed a consistent and early rise of IL-10, IL-5, and GM-CSF. These increases were rapidly reversible after discontinuation of IL-2 therapy. The inducibility of IL-10, IL-5 and GM-CSF was more pronounced with increasing time from the SCT, and in the third cycle reached an order of magnitude as in high-dose IL-2 patients without SCT. Together with the abundant in vitro data, these findings may help devise a combination immunotherapy permitting stronger anti-tumor effects, but lesser adverse effects.
Background: Multiple sclerosis (MS) often affects females during reproductive years. Although generally no negative impact on fertility is assumed, only limited data are available. In addition, ...little is known about family decision-making and medical guidance during pregnancy in this population. We surveyed 172 female MS patients on women's health and MS issues related to fertility and pregnancy. Objective: To explore women's health and pregnancy related topics in women with MS. Methods: Self-report cross-sectional survey of MS patients in Washington State. To date, 412 completed questionnaires were received (return rate 94%) and data from 202 questionnaires have been entered (172 females). Results: Data from 172 female MS patients have been analyzed. The women reported irregular menstrual cycles during child-bearing years (20%), diagnosis of endometriosis (13%) and polycystic ovarian syndrome (4%). 121 women had biological children, although most had their children prior to MS diagnosis. 25 women became pregnant after being diagnosed with MS. 60% of these were not on disease-modifying treatment (DMT), the remainder discontinued DMT before conception (20%) or during pregnancy (20%). 12% of these women reported relapses during pregnancy and 57% within 6 months of delivery; 65% breast-fed. MS patients received pregnancy-related information from MS specialists (18%), MS organizations (14%) or primary care physicians (7%). Conclusions: Our preliminary analysis suggests that the non-parity rate is increased in comparison with the national average (30% versus 18%). Whether this is the result of biological factors or choice is unknown. At this point, our data indicate that the rate of fertility-related health issues in women with MS may not be much different than in the general population. In agreement with the literature, the risk of relapse post-delivery is high. Extended periods off DMT due to pregnancy and breast-feeding may compromise optimal MS management. Our study highlights the reciprocal influence between women's health issues and MS. The definitive data will be presented and discussed.
Background:
Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing–remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure ...to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF’s distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile.
Objective:
To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study.
Methods:
EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory.
Results:
As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1–98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%; p < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13–0.20).
Conclusion:
Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.
Background:
Diroximel fumarate (DRF) is a novel oral fumarate approved for relapsing forms of multiple sclerosis (MS). DRF demonstrated significantly improved gastrointestinal (GI) tolerability ...versus dimethyl fumarate (DMF) with fewer days of Individual Gastrointestinal Symptom and Impact Scale (IGISIS) scores ⩾2, GI adverse events (AEs), and treatment discontinuations due to GI AEs. Our aim was to evaluate the impact of GI tolerability events on quality of life (QoL) for patients with relapsing–remitting MS who received DRF or DMF in EVOLVE-MS-2.
Methods:
A post hoc analysis was conducted in patients who were enrolled in the randomized, blinded, 5-week, EVOLVE-MS-2 ClinicalTrials.gov identifier: NCT03093324 study of DRF versus DMF. Patients completed daily IGISIS and Global GISIS (GGISIS) eDiary questionnaires to assess GI symptom intensity and interference with daily activities and work.
Results:
In total, 504 patients (DRF, n = 253; DMF, n = 251) received study drug and 502 (DRF, n = 253; DMF, n = 249) completed at least one post-baseline questionnaire. With DRF, GI symptoms were less likely to interfere ‘quite a bit’ or ‘extremely’ with regular daily activities IGISIS: DRF, 9.5% (24/253) versus DMF, 28.9% (72/249) or work productivity GGISIS: DRF, 6.1% (10/165) versus DMF, 11.3% (18/159). DRF-treated patients had fewer days with ⩾1 h of missed work (DRF, 43 days, n = 20 versus DMF, 88 days, n = 26). DMF-treated patients reported highest GI symptom severity and missed work at week 2–3 shortly after completing the titration period, which coincided with the majority of GI-related treatment discontinuations 58.3% (7/12). GI tolerability AEs DRF, 34.8% (88/253); DMF, 48.2% (121/251), concomitant symptomatic medication use DRF, 19.3% (17/88) versus DMF, 30.6% (37/121), and GI-related discontinuations (DRF, 0.8% versus DMF, 4.8%) were lower with DRF versus DMF.
Conclusions:
The improved GI tolerability with DRF translated into clinically meaningful benefits to QoL, as patients experienced less impact on daily life and work and required less concomitant symptomatic medication use.
Trial registration:
ClinicalTrials.gov identifier: NCT03093324
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