Impact of Pretransplant Salvage Therapies on Outcome of Hodgkin Lymphoma Patients Performing Allogeneic Transplant.

BACKGROUND: Allogeneic transplant is an effective salvage therapy in patients with Hodgkin lymphoma (HL) relapsed or refractory (R/R) to previous treatments. In recent years, immunotherapies (conjugated antibody and checkpoint inhibitors [CPI]) showed interesting results and were used as bridge therapies to allotransplant. AIM: The aim of this retrospective study in Lazio region was to evaluate the impact of these new therapies on outcome after allogeneic hematopoietic stem cell transplantation (allo-SCT) in comparison with standard chemotherapies used in the past. METHODS: We selected all consecutive patients with diagnosis of HL transplanted in four hematology transplant units, and we collected data obtained from patients' records concerning all the treatments before allo-SCT. RESULTS: A total of 56 patients were enrolled in this study. All patients underwent allo-SCT for R/R HL. Seventeen patients (30%) received chemotherapy prior to allo-SCT (group B); they were treated between 2008 and 2015; and 39 patients (70%) received brentuximab vedotin (BV), CPI, or both before allo-SCT as a bridge to transplant (group A); they were treated between 2012 and 2020. Twenty-five patients were treated with BV alone, 2 with CPI alone, and 12 first with BV and then with CPI. No patient received concomitant BV and CPI. At 5 years from allo-SCT, overall survival (OS) was 59% and progression-free survival (PFS) was 65%. No statistical differences in OS or PFS were observed between patients in groups A and B. Relapse was significantly associated with a lower survival. The only factor associated with a reduced risk of relapse was development of any grade acute graft versus host disease (GVHD) (p > 0.02). CONCLUSIONS: This regional real-world experience shows the changes that have taken place in the last 10 years in R/R HL using new drugs to render a patient eligible for allo-SCT. This strategy appears to guarantee an impressive disease control with an increased risk of complications, for example, aGVHD, that appear to nullify this advantage at least in part.

Long-term follow-up of pediatric MS patients starting treatment with injectable first-line agents: A multicentre, Italian, retrospective, observational study.

BACKGROUND: Few data are available on very long-term follow-up of pediatric multiple sclerosis (MS) patients treated with disease modifying treatments (DMTs). OBJECTIVES: To present a long-term follow-up of a cohort of Pediatric-MS patients starting injectable first-line agents. METHODS: Data regarding treatments, annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, and serious adverse event were collected. Baseline characteristics were tested in multivariate analysis to identify predictors of disease evolution. RESULTS: In total, 97 patients were followed for 12.5 ± 3.3 years. They started therapy at 13.9 ± 2.1 years, 88 with interferons and 9 with copaxone. During the whole follow-up, 82 patients changed therapy, switching to immunosuppressors/second-line treatment in 58% of cases. Compared to pre-treatment phase, the ARR was significantly reduced during the first treatment (from 3.2 ± 2.6 to 0.7 ± 1.5, p < 0.001), and it remained low during the whole follow-up (0.3 ± 0.2, p < 0.001). At last observation, 40% had disability worsening, but EDSS score remained <4 in 89%. One patient died at age of 23 years due to MS. One case of natalizumab-related progressive multifocal encephalopathy (PML) was recorded. Starting therapy before 12 years of age resulted in a better course of disease in multivariate analysis. CONCLUSION: Pediatric-MS patients benefited from interferons/copaxone, but the majority had to switch to more powerful drugs. Starting therapy before 12 years of age could lead to a more favorable outcome.

Predicting the profile of increasing disability in multiple sclerosis.

BACKGROUND: Effective therapeutic strategies to preserve function and delay progression in multiple sclerosis (MS) require early recognition of individual disease trajectories. OBJECTIVES: To determine the profiles of disability evolution, identify their early predictors and develop a risk score of increasing disability. METHODS: We analysed demographic, clinical and magnetic resonance imaging (MRI) data from patients with relapsing MS, Expanded Disability Status Scale (EDSS) score of 3.0-4.0 and follow-up ≥ 2 years. Attaining EDSS = 6.0 defined increasing disability; relapses and/or MRI defined disease activity. RESULTS: In total, 344 out of 542 (63.5%) patients reached EDSS ≥ 6.0; of these, 220 (64.0%) showed disease activity. In patients with activity, the number of relapses before reaching EDSS 3.0-4.0 predicted increasing disability; age > 45 at baseline predicted increasing disability without activity. Combining age and number of relapses increased the risk of and shortened the time to EDSS = 6.0. CONCLUSION: Increasing disability is frequently associated with persistent activity. The high number of relapses identifies early those patients worsening in the presence of activity. Age predicts increasing disability in the absence of activity. The presence of both factors increases the risk of developing severe disability. As this study likely describes the transition to progression, our findings contribute to improving patient management and stratification in trials on progressive MS.

Lesion symptom map of cognitive-postural interference in multiple sclerosis.

OBJECTIVE: To investigate the disease-altered structure-function relationship underlying the cognitive-postural interference (CPI) phenomenon in multiple sclerosis (MS). METHODS: We measured postural sway of 96 patients and 48 sex-/age-matched healthy controls by force platform in quiet standing (single-task (ST)) while performing the Stroop test (dual-task (DT)) to estimate the dual-task cost (DTC) of balance. In patient group, binary T2 and T1 lesion masks and their corresponding lesion volumes were obtained from magnetic resonance imaging (MRI) of brain. Normalized brain volume (NBV) was also estimated by SIENAX. Correlations between DTC and lesion location were determined by voxel-based lesion symptom mapping (VLSM) analyses. RESULTS: Patients had greater DTC than controls ( p < 0.001). Among whole brain MRI metrics, only T1 lesion volume correlated with DTC ( r = -0.27; p < 0.01). However, VLSM analysis did not reveal any association with DTC using T1 lesion masks. By contrast, we found clusters of T2 lesions in distinct anatomical regions (anterior and superior corona radiata, bilaterally) to be correlated with DTC ( p < 0.01 false discovery rate (FDR)-corrected). A multivariable stepwise regression model confirmed findings from VLSM analysis. NBV did not contribute to fit the model. CONCLUSION: Our findings suggest that the CPI phenomenon in MS can be explained by disconnection along specific areas implicated in task-switching abilities and divided attention.

High risk of early conversion to multiple sclerosis in clinically isolated syndromes with dissemination in space at baseline.

INTRODUCTION: Multiple sclerosis (MS) usually presents at onset with a clinically isolated syndrome (CIS). According to 2010 McDonald criteria, a diagnosis of MS can be made if CIS patients satisfy clinical/MRI criteria of both dissemination in time (DIT) and space (DIS). OBJECTIVE: The aim of this study was to analyze the follow-up data and possible prognostic factors of CIS patients satisfying DIS MRI criteria. PATIENTS AND METHODS: We performed a retrospective, multicenter study across 2 Italian centers. Clinical, MRI, and laboratory assessments were performed according to real-life clinical workup. RESULTS: Out of the 137 enrolled patients, during a median follow-up time of 3.1years, 116 (84.7%) converted to MS with the large majority (78.4%) of the converters developing MS within 1year. In multivariate analysis, baseline predictors of an earlier conversion were a cerebellar/brainstem CIS (HR 2.00, 95% CI: 1.3-3.0, p=0.001) and the presence of all the Barkhof-Tintore MRI criteria (HR 1.67, 95% CI: 1.1-2.6, p=0.028). CONCLUSIONS: Patients with CIS and DIS are at very high risk of an early conversion to MS. The onset with cerebellar/brainstem symptoms and the evidence of a higher MRI lesion load at baseline are the strongest independent predictors of an early conversion to MS.

Effect on Cognition of Estroprogestins Combined with Interferon Beta in Multiple Sclerosis: Analysis of Secondary Outcomes from a Randomised Controlled Trial.

INTRODUCTION: Cognitive impairment is a disabling symptom in multiple sclerosis (MS). While its management remains challenging, beneficial effects on cognition of interferon beta (IFN-ß) have been reported and a positive effect from estroprogestins has been hypothesised, suggesting that the combination of the two medications in women with MS could offer a promising treatment strategy. OBJECTIVES: We investigated whether a combination of estroprogestins and IFN-ß can improve cognition in women with MS. METHODS: Women with relapsing-remitting (RR) MS were randomly assigned (1:1:1) to receive subcutaneous IFN-ß-1a (Rebif®, Merck Serono, Geneva, Switzerland) 44 mcg three times a week (tiw) (group 1), subcutaneous IFN-ß-1a 44 mcg tiw plus ethinyl estradiol 20 mcg and desogestrel 150 mcg (Mercilon®, MSD Italia SRL, Rome, Italy) (group 2) or subcutaneous IFN-ß-1a 44 mcg tiw plus ethinyl estradiol 40 mcg and desogestrel 125 mcg (Gracial®, Organon Italia S.p.A., Rome, Italy) (group 3) in a randomised controlled trial, for which we report the analysis of secondary outcomes. At baseline and at 24 months, all patients underwent magnetic resonance imaging (MRI) and a comprehensive cognitive assessment, including Rao's Brief Repeatable Battery (RBRB) and questionnaires for depression, fatigue and quality of life. Failure in at least two of the RBRB tests defined 'cognitive impairment'. RESULTS: At baseline, there was no difference in the proportion of cognitively impaired patients. At month 24, the proportion of patients with cognitive impairment was lower in group 3 (34.8%) than in group 1 (47.6%) (p = 0.03). The risk of developing cognitive impairment over 24 months was lower in group 3 (p = 0.02). Mood and fatigue scores were comparable across the groups over time at both time points. However, at month 24, group 3 showed worsening on the sexual function subscale of the 54-item MS quality-of-life questionnaire (p = 0.03). CONCLUSIONS: This study suggests that the combination of high-dose estroprogestins and IFN-ß may have positive effects on cognition. However, the effect of this treatment on sexual function requires caution to be exercised. Protocol Number NCT00151801, registered in ClinicalTrials.gov.

A lesion topography-based approach to predict the outcomes of patients with multiple sclerosis treated with Interferon Beta.

BACKGROUND: With increasing availability of effective disease-modifying treatments for multiple sclerosis (MS), an early identification of patients who do not adequately respond to Interferon Beta (IFNB) is relevant to decide the future strategy. OBJECTIVE: To investigate the predictive role of new lesion location on the risk of breakthrough disease in IFNB-treated patients with MS. METHODS: We analysed data from 392 patients starting IFNB and regularly followed up to 5 years. Before and after one year of IFNB treatment, all patients underwent a conventional brain and spinal cord magnetic resonancer imaging (MRI) scan with the same 1.5T magnet to obtain the count and location of new MRI lesions. Relapses and MRI activity occurred in the first year of IFNB treatment (year 0-1) were included in the set of potential predictors for relapses and disability worsening in the subsequent four years (year 2-5). RESULTS: We found that 96 (24.5%) patients had relapses and/or MRI activity in the first year of IFNB treatment, while 41.6% of the patients experienced relapses and 17.8% experienced disability worsening. from year 2 to 5. The risk of relapses (year 2-5) was associated with ≥2 relapses (HR=5.65, p<0.001) and new T2-hyperintense lesions (for 2 new lesions: HR=1.96, p=0.011; for ≥3 new lesions: HR=3.55, p<0.001) in the first year of treatment. Other than male sex (HR=2.01, p=0.01) and higher EDSS score (HR=2.17, p<0.001), the risk of disability worsening (year 2-5) was associated with ≥2 relapses (HR=4.33, p<0.001) and new spinal cord or infratentorial lesions (HR=4.45,p<0.001) in the first year of treatment. CONCLUSIONS: Our findings suggest a dose-effect relationship between the lesion count and the risk of future relapses, while the occurrence of new MRI lesions in sites representing anatomical bottle-necks was better than lesion count at predicting the future risk of disability worsening despite IFNB treatment.

Long-term assessment of No Evidence of Disease Activity with natalizumab in relapsing multiple sclerosis.

In this study we assessed the proportion of patients with relapsing multiple sclerosis (R-MS) who had No Evidence of Disease Activity (NEDA-3), defined as absence of relapses, absence of confirmed disability worsening, and absence of radiological activity (detected by magnetic resonance imaging of the brain and spinal cord) up to 7years after starting natalizumab. Out of 152 patients considered, 58 were still on treatment and 94 discontinued treatment after a median time of 3years. According to an intention-to-treat approach, 52 (34%) patients maintained the NEDA status at the end of follow-up. The proportion of patients with NEDA increases to 41% after excluding from the analysis 64 patients who discontinued natalizumab due to concerns about progressive multifocal leukoencephalopathy. Our findings suggest that natalizumab may ensure higher proportion of patients achieving sustained long-term disease remission than that previously reported with self-injectable treatments (<10%).

The effect of inflammation and its reduction on brain plasticity in multiple sclerosis: MRI evidence.

Brain plasticity is the basis for systems-level functional reorganization that promotes recovery in multiple sclerosis (MS). As inflammation interferes with plasticity, its pharmacological modulation may restore plasticity by promoting desired patterns of functional reorganization. Here, we tested the hypothesis that brain plasticity probed by a visuomotor adaptation task is impaired with MS inflammation and that pharmacological reduction of inflammation facilitates its restoration. MS patients were assessed twice before (sessions 1 and 2) and once after (session 3) the beginning of Interferon beta (IFN beta), using behavioural and structural MRI measures. During each session, 2 functional MRI runs of a visuomotor task, separated by 25-minutes of task practice, were performed. Within-session between-run change in task-related functional signal was our imaging marker of plasticity. During session 1, patients were compared with healthy controls. Comparison of patients' sessions 2 and 3 tested the effect of reduced inflammation on our imaging marker of plasticity. The proportion of patients with gadolinium-enhancing lesions reduced significantly during IFN beta. In session 1, patients demonstrated a greater between-run difference in functional MRI activity of secondary visual areas and cerebellum than controls. This abnormally large practice-induced signal change in visual areas, and in functionally connected posterior parietal and motor cortices, was reduced in patients in session 3 compared with 2. Our results suggest that MS inflammation alters short-term plasticity underlying motor practice. Reduction of inflammation with IFN beta is associated with a restoration of this plasticity, suggesting that modulation of inflammation may enhance recovery-oriented strategies that rely on patients' brain plasticity. Hum Brain Mapp 37:2431-2445, 2016. © 2016 Wiley Periodicals, Inc.

The dual task-cost of standing balance affects quality of life in mildly disabled MS people.

The aim of this study was to explore the correlations between the dual-task cost (DTC) of standing balance and quality of life (QoL) in mildly disabled patients with multiple sclerosis (MS). In this cross-sectional study, patients affected by MS with an expanded disability status scale (EDSS) score of 3.0 or less and without an overt balance impairment were tested by means of static posturography under eyes-opened (single-task condition) and while performing the Stroop word-color test (dual-task condition), to estimate the DTC of standing balance. The self-reported 54-item MS quality of life questionnaire (MSQoL-54) was also administered to obtain a MS-specific assessment of health-related QoL. Among the 120 screened patients, 75 (53 women, 22 men) were tested. Although there was no impact of the DTC of standing balance on the physical and mental composite scores of MSQoL-54, patients who had a greater DTC of standing balance scored worse on role limitations due to physical problems (p = 0.007) and social function (p < 0.001), irrespective of demographic and other clinical characteristics including walking performance and cognitive status. However, the EDSS step and fatigue also contributed to reduced scores in these two QoL domains (p-values < 0.01). In conclusion, the phenomenon of cognitive-motor interference, investigated as DTC of standing balance, may affect specific QoL domains even in mildly disabled patients with MS and in the absence of an overt balance dysfunction.

Multiple sclerosis: changes in microarchitecture of white matter tracts after training with a video game balance board.

PURPOSE: To determine if high-intensity, task-oriented, visual feedback training with a video game balance board (Nintendo Wii) induces significant changes in diffusion-tensor imaging ( DTI diffusion-tensor imaging ) parameters of cerebellar connections and other supratentorial associative bundles and if these changes are related to clinical improvement in patients with multiple sclerosis. MATERIALS AND METHODS: The protocol was approved by local ethical committee; each participant provided written informed consent. In this 24-week, randomized, two-period crossover pilot study, 27 patients underwent static posturography and brain magnetic resonance (MR) imaging at study entry, after the first 12-week period, and at study termination. Thirteen patients started a 12-week training program followed by a 12-week period without any intervention, while 14 patients received the intervention in reverse order. Fifteen healthy subjects also underwent MR imaging once and underwent static posturography. Virtual dissection of white matter tracts was performed with streamline tractography; values of DTI diffusion-tensor imaging parameters were then obtained for each dissected tract. Repeated measures analyses of variance were performed to evaluate whether DTI diffusion-tensor imaging parameters significantly changed after intervention, with false discovery rate correction for multiple hypothesis testing. RESULTS: There were relevant differences between patients and healthy control subjects in postural sway and DTI diffusion-tensor imaging parameters (P < .05). Significant main effects of time by group interaction for fractional anisotropy and radial diffusivity of the left and right superior cerebellar peduncles were found (F2,23 range, 5.555-3.450; P = .036-.088 after false discovery rate correction). These changes correlated with objective measures of balance improvement detected at static posturography (r = -0.381 to 0.401, P < .05). However, both clinical and DTI diffusion-tensor imaging changes did not persist beyond 12 weeks after training. CONCLUSION: Despite the low statistical power (35%) due to the small sample size, the results showed that training with the balance board system modified the microstructure of superior cerebellar peduncles. The clinical improvement observed after training might be mediated by enhanced myelination-related processes, suggesting that high-intensity, task-oriented exercises could induce favorable microstructural changes in the brains of patients with multiple sclerosis.