Alemtuzumab treatment for multiple sclerosis in Austria: An observational long-term outcome study.

BACKGROUND/OBJECTIVE: Observational real-world study to analyze the clinical effects of alemtuzumab (ALEM) and subsequent disease-modifying therapy (DMT) usage in multiple sclerosis (MS). METHODS: Data retrieved from the Austrian MS treatment registry (AMSTR) included baseline (BL) characteristics (at ALEM start), annualized relapse rate (ARR), 6-month confirmed progression independent of relapse activity (PIRA; ≥ 0.5-point Expanded Disability Status Scale (EDSS) score increase), 6-month confirmed disability improvement (CDI; ≥ 0.5-point EDSS decrease), and safety outcomes until initiation of a subsequent DMT. The EDSS was re-baselined at 30 days from ALEM start (BL EDSS). RESULTS: Eighty-seven ALEM-treated patients (median age: 32 years, 72% female, 14% treatment-naïve) were followed for a median of 55 (interquartile range 31-68) months. We found significant reductions in the ARR from 1.16 before ALEM to 0.15 throughout Years 1-9 (p < 0.001). Subsequent DMTs were initiated in 19 patients (22%, 74% anti-CD20 monoclonal antibodies). At Year 5 (n = 53), more patients achieved CDI (58%, 95% confidence interval (CI) 45%-71%) than had experienced PIRA (14%, CI 7.5%-24%), and 58% remained relapse-free. Shorter MS duration (p < 0.001, hazard ratio (HR) 0.86 (CI 0.80-0.93)) and no previous high-efficacy treatment (p < 0.001, HR 5.16 (CI 2.66-10.0)) were the best predictors of CDI, while PIRA was associated with a higher number of previous DMTs (p = 0.04, HR 3.06, CI 1.05-8.89). We found no new safety signals. INTERPRETATION: ALEM had long-lasting beneficial effects on the ARR and disability improvement, especially when initiated early in the course of the disease. Only a subset of patients received subsequent DMTs.

Long-Term Effects of Alemtuzumab on CD4+ Lymphocytes in Multiple Sclerosis Patients: A 72-Month Follow-Up.

Introduction: Alemtuzumab is highly effective in the treatment of patients with relapsing multiple sclerosis (PwRMS) and selectively targets the CD52 antigen, with a consequent profound lymphopenia, particularly of CD4+ T lymphocytes. However, the immunological basis of its long-term efficacy has not been clearly elucidated. Methods: We followed up 29 alemtuzumab-treated RMS patients over a period of 72 months and studied the immunological reconstitution of their CD4+ T cell subsets by means of phenotypic and functional analysis and through mRNA-related molecule expression, comparing them to healthy subject (HS) values (rate 2:1). Results: In patients receiving only two-course alemtuzumab, the percentage of CD4+ lymphocytes decreased and returned to basal levels only at month 48. Immune reconstitution of the CD4+ subsets was characterized by a significant increase (p < 0.001) in Treg cell percentage at month 24, when compared to baseline, and was accompanied by restoration of the Treg suppressor function that increased within a range from 2- to 6.5-fold compared to baseline and that persisted through to the end of the follow-up. Furthermore, a significant decrease in self-reactive myelin basic protein-specific Th17 (p < 0.0001) and Th1 (p < 0.05) cells reaching HS values was observed starting from month 12. There was a change in mRNA of cytokines, chemokines, and transcriptional factors related to Th17, Th1, and Treg cell subset changes, consequently suggesting a shift toward immunoregulation and a reduction of T cell recruitment to the central nervous system. Conclusions: These data provide further insight into the mechanism that could contribute to the long-term 6-year persistence of the clinical effect of alemtuzumab on RMS disease activity.

Anti-CD52 antibody treatment in murine experimental autoimmune encephalomyelitis induces dynamic and differential modulation of innate immune cells in peripheral immune and central nervous systems.

Anti-CD52 antibody (anti-CD52-Ab) leads to a rapid depletion of T and B cells, followed by reconstitution of immune cells with tolerogenic characteristics. However, very little is known about its effect on innate immune cells. In this study, experimental autoimmune encephalomyelitis mice were administered murine anti-CD52-Ab to investigate its effect on dendritic cells and monocytes/macrophages in the periphery lymphoid organs and the central nervous system (CNS). Our data show that blood and splenic innate immune cells exhibited significantly increased expression of MHC-II and costimulatory molecules, which was associated with increased capacity of activating antigen-specific T cells, at first day but not three weeks after five daily treatment with anti-CD52-Ab in comparison with controls. In contrast to the periphery, microglia and infiltrating macrophages in the CNS exhibited reduced expression levels of MHC-II and costimulatory molecules after antibody treatment at both time-points investigated when compared to controls. Furthermore, the transit response of peripheral innate immune cells to anti-CD52-Ab treatment was also observed in the lymphocyte-deficient SCID mice, suggesting the changes are not a direct consequence of the mass depletion of lymphocytes in the periphery. Our study demonstrates a dynamic and tissue-specific modulation of the innate immune cells in their phenotype and function following the antibody treatment. The findings of differential modulation of the microglia and infiltrating macrophages in the CNS in comparison with the innate immune cells in the peripheral organs support the CNS-specific beneficial effect of alemtuzumab treatment on inhibiting neuroinflammation in multiple sclerosis patients.

Immune Regulatory Cell Bias Following Alemtuzumab Treatment in Relapsing-Remitting Multiple Sclerosis.

Alemtuzumab is a highly effective treatment for relapsing-remitting multiple sclerosis. It selectively targets the CD52 antigen to induce profound lymphocyte depletion, followed by recovery of T and B cells with regulatory phenotypes. We previously showed that regulatory T cell function is restored with cellular repletion, but little is known about the functional capacity of regulatory B-cells and peripheral blood monocytes during the repletion phase. In this study (ClinicalTrials.gov ID# NCT03647722) we simultaneously analyzed the change in composition and function of both regulatory lymphocyte populations and distinct monocyte subsets in cross-sectional cohorts of MS patients prior to or 6, 12, 18, 24 or 36 months after their first course of alemtuzumab treatment. We found that the absolute number and percentage of cells with a regulatory B cell phenotype were significantly higher after treatment and were positivity correlated with regulatory T cells. In addition, B cells from treated patients secreted higher levels of IL-10 and BDNF, and inhibited the proliferation of autologous CD4+CD25- T cell targets. Though there was little change in monocytes populations overall, following the second annual course of treatment, CD14+ monocytes had a significantly increased anti-inflammatory bias in cytokine secretion patterns. These results confirmed that the immune system in alemtuzumab-treated patients is altered in favor of a regulatory milieu that involves expansion and increased functionality of multiple regulatory populations including B cells, T cells and monocytes. Here, we showed for the first time that functionally competent regulatory B cells re-appear with similar kinetics to that of regulatory T-cells, whereas the change in anti-inflammatory bias of monocytes does not occur until after the second treatment course. These findings justify future studies of all regulatory cell types following alemtuzumab treatment to reveal further insights into mechanisms of drug action, and to identify key immunological predictors of durable clinical efficacy in alemtuzumab-treated patients.

Multiple sclerosis: structural and functional integrity of the visual system following alemtuzumab therapy.

OBJECTIVE: To investigate potential neuroprotective and pro-remyelinating effects of alemtuzumab in multiple sclerosis (MS), using the visual pathway as a model. METHODS: We monitored clinical, multifocal visual evoked potential (mfVEP) and MRI outcomes in 30 patients commencing alemtuzumab for relapsing MS, and a reference group of 20 healthy controls (HCs), over 24 months. Change in mfVEP latency was the primary endpoint; change in optic radiation (OR) lesion diffusion metrics and Mars letter contrast sensitivity over the course of the study were secondary endpoints. RESULTS: In patients, we observed a mean shortening of mfVEP latency of 1.21 ms over the course of the study (95% CI 0.21 to 2.21, p=0.013), not altered by correction for age, gender, disease duration or change in OR T2 lesion volume. Mean mfVEP latency in the HC group increased over the course of the study by 0.72 ms (not significant). Analysis of chronic OR T2 lesions (patients) showed an increase in normalised fractional anisotropy and axial diffusivity between baseline and 24 months (both p<0.01). Mean Mars letter contrast sensitivity was improved at 24 months vs baseline (p<0.001), and driven by an early improvement, in both patients and HC. CONCLUSION: We found evidence of partial lesion remyelination after alemtuzumab therapy, indicating either natural restoration in the context of a 'permissive' local milieu; or potentially an independent, pro-reparative mechanism of action. The visual system presents a unique opportunity to study function-structure specific effects of therapy and inform the design of future phase 2 MS remyelination trials.

aHSCT is superior to alemtuzumab in maintaining NEDA and improving cognition in multiple sclerosis.

OBJECTIVE: Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly recognized as a potential therapy for patients with highly active multiple sclerosis (MS). This study aims to assess outcome differences in disease activity in MS patients treated either with aHSCT or alemtuzumab. METHODS: We conducted a monocentric registry-based cohort study by recording the clinical course (EDSS and relapses), MRI parameters (new T2 lesions), and neuropsychological assessment in all 19 MS patients receiving aHSCT, and all 21 patients receiving alemtuzumab between 2007 and 2018. We used survival analyses of no evidence of disease activity (NEDA) as the primary objective which was defined by no EDSS progression, no relapse, and no new T2 lesion on MRI. Secondary objectives were EDSS improvement and neurocognitive performance. RESULTS: Both treatment groups were similar in respect of age, gender, disability, and neurocognitive performance except for significantly longer disease duration in the alemtuzumab group. Mean follow-up was 58.8 [range 29-140] months in the aHSCT group compared to 27.6 [range 11-52] months in the alemtuzumab-treated group. We observed significantly more patients maintaining NEDA in the aHSCT group (p = 0.048) compared to the alemtuzumab-treated patients. Furthermore, 37% of the aHSCT patients showed an improvement of EDSS compared to none in the alemtuzumab-treated group (p = 0.033). It is of note that cognitive function was significantly improved in the aHSCT-treated patients. INTERPRETATION: aHSCT suppresses inflammatory activity more effectively than alemtuzumab and might enable improvement of overall disability and cognition in MS.

CD52-targeted depletion by Alemtuzumab ameliorates allergic airway hyperreactivity and lung inflammation.

Allergic asthma is a chronic inflammatory disorder associated with airway hyperreactivity (AHR) whose global prevalence is increasing at an alarming rate. Group 2 innate lymphoid cells (ILC2s) and T helper 2 (TH2) cells are producers of type 2 cytokines, which may contribute to development of AHR. In this study, we explore the potential of CD52-targeted depletion of type 2 immune cells for treating allergic AHR. Here we show that anti-CD52 therapy can prevent and remarkably reverse established IL-33-induced AHR by reducing airway resistance and alleviating lung inflammation. We further show that CD52 depletion prevents and treats allergic AHR induced by clinically relevant allergens such as Alternaria alternata and house dust mite. Importantly, we leverage various humanized mice models of AHR to show new therapeutic applications for Alemtuzumab, an anti-CD52 depleting antibody that is currently FDA approved for treatment of multiple sclerosis. Our results demonstrate that CD52 depletion is a viable therapeutic option for reduction of pulmonary inflammation, abrogation of eosinophilia, improvement of lung function, and thus treatment of allergic AHR. Taken together, our data suggest that anti-CD52 depleting monoclonal antibodies, such as Alemtuzumab, can serve as viable therapeutic drugs for amelioration of TH2- and ILC2-dependent AHR.

Alemtuzumab: A Review in Relapsing Remitting Multiple Sclerosis.

Alemtuzumab (Lemtrada®) is an anti-CD52 monoclonal antibody approved in the EU for the treatment of highly active relapsing-remitting multiple sclerosis (RRMS). In phase 3 trials in patients with active RRMS, intravenous alemtuzumab was more effective than subcutaneous interferon ß-1a in terms of decreasing relapse rates (in treatment-naïve or -experienced patients) and disability progression (treatment-experienced patients). Treatment benefits were maintained over up to 9 years of follow-up, with ≈ 50% of patients not requiring retreatment. The efficacy of alemtuzumab in patients with highly active disease was generally similar to that in the overall population. Alemtuzumab has an acceptable tolerability profile, with infusion-associated reactions, infections and autoimmunity being the main safety and tolerability issues. Current evidence indicates that alemtuzumab is an effective treatment option for adults with highly active RRMS, with an acceptable safety and tolerability profile and convenient treatment regimen.

The blood endothelial cell chamber - An innovative system to study immune responses in drug development.

The risk for adverse immune-mediated reactions, associated with the administration of certain immunotherapeutic agents, should be mitigated early. Infusion reactions to monoclonal antibodies and other biopharmaceuticals, known as cytokine release syndrome, can arise from the release of cytokines via the drug target cell, as well as the recruitment of immune effector cells. While several in vitro cytokine release assays have been proposed up to date, many of them lack important blood components, required for this response to occur. The blood endothelial cell chamber model is an in vitro assay, composed of freshly drawn human whole blood and cultured human primary endothelial cells. Herein, its potential to study the compatibility of immunotherapeutics with the human immune system was studied by evaluating three commercially available monoclonal antibodies and bacterial endotoxin lipopolysaccharide. We demonstrate that the anti-CD28 antibody TGN1412 displayed an adaptive cytokine release profile and a distinct IL-2 response, accompanied with increased CD3+ cell recruitment. Alemtuzumab exhibited a clear cytokine response with a mixed adaptive/innate source (IFNγ, TNFα and IL-6). Its immunosuppressive nature is observed in depleted CD3+ cells. Cetuximab, associated with low infusion reactions, showed a very low or absent stimulatory effect on proinflammatory cytokines. In contrast, bacterial endotoxin demonstrated a clear innate cytokine response, defined by TNFα, IL-6 and IL-1ß release, accompanied with a strong recruitment of CD14+CD16+ cells. Therefore, the blood endothelial cell chamber model is presented as a valuable in vitro tool to investigate therapeutic monoclonal antibodies with respect to cytokine release and vascular immune cell recruitment.

Effect of alemtuzumab-based T-cell depletion on graft compositional change in vitro and immune reconstitution early after allogeneic stem cell transplantation.

BACKGROUND AIMS: To reduce the risk of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloSCT), T-cell depletion (TCD) of grafts can be performed by the addition of alemtuzumab (ALT) "to the bag" (in vitro) before transplantation. In this prospective study, the authors analyzed the effect of in vitro incubation with 20 mg ALT on the composition of grafts prior to graft infusion. Furthermore, the authors assessed whether graft composition at the moment of infusion was predictive for T-cell reconstitution and development of GVHD early after TCD alloSCT. METHODS: Sixty granulocyte colony-stimulating factor-mobilized stem cell grafts were obtained from ≥9/10 HLA-matched related and unrelated donors. The composition of the grafts was analyzed by flow cytometry before and after in vitro incubation with ALT. T-cell reconstitution and incidence of severe GVHD were monitored until 12 weeks after transplantation. RESULTS: In vitro incubation of grafts with 20 mg ALT resulted in an initial median depletion efficiency of T-cell receptor (TCR) α/ß T cells of 96.7% (range, 63.5-99.8%), followed by subsequent depletion in vivo. Graft volumes and absolute leukocyte counts of grafts before the addition of ALT were not predictive for the efficiency of TCR α/ß T-cell depletion. CD4pos T cells were depleted more efficiently than CD8pos T cells, and naive and regulatory T cells were depleted more efficiently than memory and effector T cells. This differential depletion of T-cell subsets was in line with their reported differential CD52 expression. In vitro depletion efficiencies and absolute numbers of (naive) TCR α/ß T cells in the grafts after ALT incubation were not predictive for T-cell reconstitution or development of GVHD post- alloSCT. CONCLUSIONS: The addition of ALT to the bag is an easy, fast and generally applicable strategy to prevent GVHD in patients receiving alloSCT after myeloablative or non-myeloablative conditioning because of the efficient differential depletion of donor-derived lymphocytes and T cells.

Siplizumab, an Anti-CD2 Monoclonal Antibody, Induces a Unique Set of Immune Modulatory Effects Compared to Alemtuzumab and Rabbit Anti-Thymocyte Globulin In Vitro.

Antibodies are commonly used in organ transplant induction therapy and to treat autoimmune disorders. The effects of some biologics on the human immune system remain incompletely characterized and a deeper understanding of their mechanisms of action may provide useful insights for their clinical application. The goal of this study was to contrast the mechanistic properties of siplizumab with Alemtuzumab and rabbit Anti-Thymocyte Globulin (rATG). Mechanistic assay systems investigating antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell phagocytosis and complement-dependent cytotoxicity were used to characterize siplizumab. Further, functional effects of siplizumab, Alemuzumab, and rATG were investigated in allogeneic mixed lymphocyte reaction. Changes in T cell activation, T cell proliferation and frequency of naïve T cells, memory T cells and regulatory T cells induced by siplizumab, Alemtuzumab and rATG in allogeneic mixed lymphocyte reaction were assessed via flow cytometry. Siplizumab depleted T cells, decreased T cell activation, inhibited T cell proliferation and enriched naïve and bona fide regulatory T cells. Neither Alemtuzumab nor rATG induced the same combination of functional effects. The results presented in this study should be used for further in vitro and in vivo investigations that guide the clinical use of immune modulatory biologics.

Mutations in PIGA cause a CD52-/GPI-anchor-deficient phenotype complicating alemtuzumab treatment in T-cell prolymphocytic leukemia.

OBJECTIVE: Infusional alemtuzumab followed by consolidating allogeneic hematopoietic stem cell transplantation in eligible patients is considered a standard of care in T-cell prolymphocytic leukemia (T-PLL). Antibody selection against CD52 has been associated with the development of CD52-negative leukemic T cells at time of relapse. Clinical implications and molecular mechanisms underlying this phenotypic switch are unknown. METHODS: We performed flow cytometry and real-time-PCR for CD52-expression and next generation sequencing for PIGA mutational analyses. RESULTS: We identified loss of CD52 expression after alemtuzumab treatment in two of 21 T-PLL patients resulting from loss of GPI-anchor expression caused by inactivating mutations of the PIGA gene. One patient with relapsed T-PLL exhibited a single PIGA mutation, causing a CD52-negative escape variant of the initial leukemic cell clone, preventing alemtuzumab-retreatment. The second patient with continued complete remission after alemtuzumab treatment harbored three different PIGA mutations that affected either the non-neoplastic T cell or the mononuclear cell compartment and resulted in symptomatic paroxysmal nocturnal hemoglobinuria. Next generation sequencing of T-PLL cells collected before the initiation of treatment revealed PIGA wild-type sequence reads in all 16 patients with samples available for testing. CONCLUSION: These data indicate that PIGA mutations were acquired during or after completion of alemtuzumab treatment.

Mitigating alemtuzumab-associated autoimmunity in MS: A "whack-a-mole" B-cell depletion strategy.

OBJECTIVE: To determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19+ B cells approximates 40%-50% of baseline levels as measured before alemtuzumab treatment inception), can mitigate alemtuzumab-associated secondary autoimmunity. METHODS: In this hypothesis-driven pilot study, 10 patients received low-dose rituximab (50-150 mg/m2), a chimeric anti-CD20 monoclonal antibody, after either their first or second cycles of alemtuzumab. These patients were then routinely assessed for the development of autoimmune disorders and safety signals related to the use of dual monoclonal antibody therapy. RESULTS: Five patients received at least 1 IV infusion of low-dose rituximab, following alemtuzumab therapy, with a mean follow-up of 41 months. None of the 5 patients developed secondary autoimmune disorders. An additional 5 patients with follow-up over less than 24 months received at least 1 infusion of low-dose rituximab treatment following alemtuzumab treatment. No secondary autoimmune diseases were observed. CONCLUSIONS: An anti-CD20 "whack-a-mole" B-cell depletion strategy may serve to mitigate alemtuzumab-associated secondary autoimmunity in MS by reducing the imbalance in B- and T-cell regulatory networks during immune reconstitution. We believe that these observations warrant further investigation. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for people with MS, low-dose rituximab following alemtuzumab treatment decreases the risk of alemtuzumab-associated secondary autoimmune diseases.

Anti-CD52 blocks EAE independent of PD-1 signals and promotes repopulation dominated by double-negative T cells and newly generated T and B cells.

Lymphocyte depletion using anti-CD52 antibody effectively reduces relapses of multiple sclerosis (MS). To begin to understand what mechanisms might control this outcome, we examined the effect of a murine-CD52-specific mAb on the depletion and repopulation of immune cells in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. We tested whether the tolerance-promoting receptor programmed cell death protein-1 (PD-1) is required for disease remission post anti-CD52, and found that PD-1-deficient mice with a more severe EAE were nevertheless effectively treated with anti-CD52. Anti-CD52 increased the proportions of newly generated T cells and double-negative (DN) T cells while reducing newly generated B cells; the latter effect being associated with a higher expression of CD52 by these cells. In the longer term, anti-CD52 caused substantial increases in the proportion of newly generated lymphocytes and DN T cells in mice with EAE. Thus, the rapid repopulation of lymphocytes from central lymphoid organs post anti-CD52 may limit further disease. Furthermore, these data identify DN T cells, a subset with immunoregulatory potential, as a significant hyperrepopulating subset following CD52-mediated depletion.

Characterization of an Anti-CD5 Directed CAR T-Cell against T-Cell Malignancies.

T-cell malignancies often result in poor prognosis and outcome for patients. Immunotherapy has recently emerged as a revolutionary treatment against cancer, and the success seen in CD19 CAR clinical trials may extend to T cell diseases. However, a shared antigen pool coupled with the impact of T-cell depletion incurred by targeting T cell disease remain concepts to be clinically explored with caution. Here we report on the ability of T cells transduced with a CD5CAR to specifically and potently lyse malignant T-cell lines and primary tumors in vitro in addition to significantly improving in vivo control and survival of xenograft models of T-ALL. To extensively explore and investigate the biological properties of a CD5 CAR, we evaluated multiple CD5 CAR constructs and constructed 3 murine models to characterize the properties of CD5 down-regulation, the efficacy and specificity produced by different CD5 CAR construct designs, and the impact of incorporating a CD52 safety switch using CAMPATH to modulate the persistency and function of CAR cells. These data support the potential use of CD5CAR T cells in the treatment of T cell malignancies or refractory disease in clinical settings.

Targeting Two Antigens Associated with B-ALL with CD19-CD123 Compound Car T Cell Therapy.

The recent FDA approval of the first CAR immunotherapy marks a watershed moment in the advancement toward a cure for cancer. CD19 CAR treatment for B cell acute lymphocytic leukemia has achieved unprecedented remission rates. However, despite success in treating previously relapsed and refractory patients, CD19 CAR faces similar challenges as traditional chemotherapy, in that malignancy can adapt and overcome treatment. The emergence of both antigen positive and negative blasts after CAR treatment represents a need to bolster current CAR approaches. Here, we report on the anti-tumor activity of a CAR T cell possessing 2 discrete scFv domains against the leukemic antigens CD19 and CD123. We determined that the resulting compound CAR (cCAR) T cell possesses consistent, potent, and directed cytotoxicity against each target antigen population both in vitro and in vivo. Our findings indicate that targeting CD19 and CD123 on B-ALL cells may be an effective strategy for augmenting the response against leukemic blasts and reducing rates of relapse.

Impact of alemtuzumab on health-related quality of life over 6 years in CARE-MS II trial extension patients with relapsing-remitting multiple sclerosis.

BACKGROUND: In CARE-MS II (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; NCT00548405), alemtuzumab (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved health-related quality of life (HRQL) outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis (RRMS) patients over 2 years. Patients completing CARE-MS II could enter a 4-year extension study (NCT00930553). OBJECTIVE: The aim of this study is to assess 6-year HRQL outcomes in alemtuzumab-treated CARE-MS II patients, including those with highly active disease (HAD). METHODS: During extension, patients could receive additional alemtuzumab for clinical/magnetic resonance imaging (MRI) activity or other disease-modifying therapies per investigator's discretion. Assessments include Functional Assessment of Multiple Sclerosis (FAMS), 36-Item Short-Form Health Survey (SF-36), and EQ-5D visual analog scale (EQ-VAS). RESULTS: Alemtuzumab-treated patients improved or stabilized all HRQL measures over 6 years with significant improvements from baseline at all time points on EQ-VAS and for up to 5 years on FAMS, SF-36 MCS, and SF-36 PCS. Alemtuzumab-treated patients with HAD showed significant improvements versus baseline at Year 2 on all HRQL measures, and significant improvements versus SC IFNB-1a on SF-36 PCS and EQ-VAS; however, the improvements did not reach the threshold for clinical relevance. CONCLUSION: Alemtuzumab-treated CARE-MS II patients improved or stabilized HRQL versus baseline over 6 years. This is the first study to show long-term HRQL benefits in patients with HAD.

Longitudinal analysis of serum neurofilament light chain: A potential therapeutic monitoring biomarker for multiple sclerosis.

OBJECTIVES: Serum neurofilament light chain (sNfL) has been proposed a potential biomarker in multiple sclerosis (MS) based on mainly cross-sectional observations in Western population. To clarify clinical implication of sNfL, we longitudinally analysed sNfL levels at multiple time points in Korean MS patients undergoing alemtuzumab therapy. METHODS: Between 2016 and 2018, 144 sera from 17 MS patients treated with alemtuzumab at National Cancer Centre and 35 sera from 35 age- and gender-matched healthy controls (HCs) were collected for a longitudinal study with a mean 21-month follow-up. The sera were measured for sNfL levels using single molecule array. Patients were classified into two groups: evidence of disease activity (EDA) or no evidence of disease activity (NEDA). RESULTS: During alemtuzumab therapy, sNfL levels in EDA patients were significantly higher than those in NEDA patients and HCs (p < 0.001). In longitudinal analysis, the sNfL levels were consistently low in NEDA patients, while it consistently increased in radiologically and/or clinically active status in EDA patients. All sNfL levels in radiologically and/or clinically active status samples were higher than those in inactive status samples. CONCLUSION: These results suggest that sNfL is a promising monitoring biomarker for personalized therapeutics in MS patients.