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The Annals of Pharmacotherapy Jul 2023To provide an overview of clinical sequelae and emerging treatment options for hemophagocytic lymphohistiocytosis (HLH). (Review)
Review
OBJECTIVE
To provide an overview of clinical sequelae and emerging treatment options for hemophagocytic lymphohistiocytosis (HLH).
DATA SOURCES
A literature search was conducted using the search terms "hemophagocytic lymphohistiocytosis," "hemophagocytic syndrome," "macrophage activation syndrome," and "treatment" on Ovid and PubMed from January 1, 2017, through September 28, 2022.
STUDY SELECTION AND DATA EXTRACTION
Relevant clinical trials, meta-analyses, case reports, review articles, package inserts, and guidelines to identify current and emerging therapeutic options for the management of HLH.
DATA SYNTHESIS
Genetic disorders and secondary causes may trigger HLH in both children and adults. Notable improvements in the diagnosis of HLH were seen with implementation of the HLH-2004 standard diagnostic criteria; however, timely and accurate identification of HLH remain significant barriers to optimal management. Multiagent immunochemotherapy are the backbone of aggressive therapy for acutely ill patients with HLH.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
The global coronavirus 2019 (COVID-19) pandemic and emerging immune effector cell therapies have served to highlight the concerns with immune dysregulation and subsequent HLH precipitation. Without prompt identification and treatment, HLH can be fatal. Historically, the clinician's armamentarium for managing HLH was sparse, with etoposide-based protocols serving as the standard of care. Relapsed or refractory disease portends a poor prognosis and requires additional treatment options. Second- or subsequent-line options now include hematopoietic stem cell transplantation, emapalumab, alemtuzumab, anakinra, ruxolitinib, and tocilizumab.
CONCLUSIONS
Improvements in diagnostic methods and novel immunosuppressive treatment strategies, including noncytotoxic immunochemotherapy, have transformed the therapeutic landscape. Unfortunately, many unanswered questions remain. Additional studies are required to optimize dosing, schedules, treatment sequences, and indications for novel treatment options.
Topics: Child; Adult; Humans; Lymphohistiocytosis, Hemophagocytic; COVID-19; Immunosuppressive Agents; Etoposide; Hematopoietic Stem Cell Transplantation
PubMed: 36349896
DOI: 10.1177/10600280221134719 -
Journal of Comparative Effectiveness... Jul 2023To assess the relative efficacy of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) including newer therapies (ozanimod, ponesimod,... (Meta-Analysis)
Meta-Analysis
To assess the relative efficacy of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) including newer therapies (ozanimod, ponesimod, ublituximab) using network meta-analysis (NMA). Bayesian NMAs for annualised relapse rate (ARR) and time to 3-month and 6-month confirmed disability progression (3mCDP and 6mCDP) were conducted. For each outcome, the three most efficacious treatments versus placebo were monoclonal antibody (mAb) therapies: alemtuzumab, ofatumumab, and ublituximab for ARR; alemtuzumab, ocrelizumab, and ofatumumab for 3mCDP; and alemtuzumab, natalizumab, and either ocrelizumab or ofatumumab (depending on the CDP definition used for included ofatumumab trials) for 6mCDP. The most efficacious DMTs for RMS were mAb therapies. Of the newer therapies, only ublituximab ranked among the three most efficacious treatments (for ARR).
Topics: Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Alemtuzumab; Network Meta-Analysis; Bayes Theorem; Recurrence
PubMed: 37265062
DOI: 10.57264/cer-2023-0016 -
International Journal of Molecular... Jul 2023T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells. Most patients with T-PLL present with lymphocytosis, anemia,... (Review)
Review
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells. Most patients with T-PLL present with lymphocytosis, anemia, thrombocytopenia, and hepatosplenomegaly. Correct identification of T-PLL is essential because treatment for this disease is distinct from that of other T-cell neoplasms. In 2019, the T-PLL International Study Group (TPLL-ISG) established criteria for the diagnosis, staging, and assessment of response to treatment of T-PLL with the goal of harmonizing research efforts and supporting clinical decision-making. T-PLL pathogenesis is commonly driven by T-cell leukemia 1 () overexpression and loss, genetic alterations that are incorporated into the TPLL-ISG diagnostic criteria. The cooperativity between family members and is seemingly unique to T-PLL across the spectrum of T-cell neoplasms. The role of the T-cell receptor, its downstream kinases, and JAK/STAT signaling are also emerging themes in disease pathogenesis and have obvious therapeutic implications. Despite improved understanding of disease pathogenesis, alemtuzumab remains the frontline therapy in the treatment of naïve patients with indications for treatment given its high response rate. Unfortunately, the responses achieved are rarely durable, and the majority of patients are not candidates for consolidation with hematopoietic stem cell transplantation. Improved understanding of T-PLL pathogenesis has unveiled novel therapeutic vulnerabilities that may change the natural history of this lymphoproliferative neoplasm and will be the focus of this concise review.
Topics: Humans; Leukemia, Prolymphocytic, T-Cell; Alemtuzumab; Hematopoietic Stem Cell Transplantation; Mutation
PubMed: 37569479
DOI: 10.3390/ijms241512106 -
The Cochrane Database of Systematic... Nov 2023Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects mainly young adults (two to three times more frequently in women than in men) and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects mainly young adults (two to three times more frequently in women than in men) and causes significant disability after onset. Although it is accepted that immunotherapies for people with MS decrease disease activity, uncertainty regarding their relative safety remains.
OBJECTIVES
To compare adverse effects of immunotherapies for people with MS or clinically isolated syndrome (CIS), and to rank these treatments according to their relative risks of adverse effects through network meta-analyses (NMAs).
SEARCH METHODS
We searched CENTRAL, PubMed, Embase, two other databases and trials registers up to March 2022, together with reference checking and citation searching to identify additional studies.
SELECTION CRITERIA
We included participants 18 years of age or older with a diagnosis of MS or CIS, according to any accepted diagnostic criteria, who were included in randomized controlled trials (RCTs) that examined one or more of the agents used in MS or CIS, and compared them versus placebo or another active agent. We excluded RCTs in which a drug regimen was compared with a different regimen of the same drug without another active agent or placebo as a control arm.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods for data extraction and pairwise meta-analyses. For NMAs, we used the netmeta suite of commands in R to fit random-effects NMAs assuming a common between-study variance. We used the CINeMA platform to GRADE the certainty of the body of evidence in NMAs. We considered a relative risk (RR) of 1.5 as a non-inferiority safety threshold compared to placebo. We assessed the certainty of evidence for primary outcomes within the NMA according to GRADE, as very low, low, moderate or high.
MAIN RESULTS
This NMA included 123 trials with 57,682 participants Serious adverse events (SAEs) Reporting of SAEs was available from 84 studies including 5696 (11%) events in 51,833 (89.9%) participants out of 57,682 participants in all studies. Based on the absolute frequency of SAEs, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 18 additional people would have a SAE compared to placebo. Low-certainty evidence suggested that three drugs may decrease SAEs compared to placebo (relative risk [RR], 95% confidence interval [CI]): interferon beta-1a (Avonex) (0.78, 0.66 to 0.94); dimethyl fumarate (0.79, 0.67 to 0.93), and glatiramer acetate (0.84, 0.72 to 0.98). Several drugs met our non-inferiority criterion versus placebo: moderate-certainty evidence for teriflunomide (1.08, 0.88 to 1.31); low-certainty evidence for ocrelizumab (0.85, 0.67 to 1.07), ozanimod (0.88, 0.59 to 1.33), interferon beta-1b (0.94, 0.78 to 1.12), interferon beta-1a (Rebif) (0.96, 0.80 to 1.15), natalizumab (0.97, 0.79 to 1.19), fingolimod (1.05, 0.92 to 1.20) and laquinimod (1.06, 0.83 to 1.34); very low-certainty evidence for daclizumab (0.83, 0.68 to 1.02). Non-inferiority with placebo was not met due to imprecision for the other drugs: low-certainty evidence for cladribine (1.10, 0.79 to 1.52), siponimod (1.20, 0.95 to 1.51), ofatumumab (1.26, 0.88 to 1.79) and rituximab (1.01, 0.67 to 1.52); very low-certainty evidence for immunoglobulins (1.05, 0.33 to 3.32), diroximel fumarate (1.05, 0.23 to 4.69), peg-interferon beta-1a (1.07, 0.66 to 1.74), alemtuzumab (1.16, 0.85 to 1.60), interferons (1.62, 0.21 to 12.72) and azathioprine (3.62, 0.76 to 17.19). Withdrawals due to adverse events Reporting of withdrawals due to AEs was available from 105 studies (85.4%) including 3537 (6.39%) events in 55,320 (95.9%) patients out of 57,682 patients in all studies. Based on the absolute frequency of withdrawals, our non-inferiority threshold (up to a 50% increased risk) meant that no more than 1 in 31 additional people would withdraw compared to placebo. No drug reduced withdrawals due to adverse events when compared with placebo. There was very low-certainty evidence (meaning that estimates are not reliable) that two drugs met our non-inferiority criterion versus placebo, assuming an upper 95% CI RR limit of 1.5: diroximel fumarate (0.38, 0.11 to 1.27) and alemtuzumab (0.63, 0.33 to 1.19). Non-inferiority with placebo was not met due to imprecision for the following drugs: low-certainty evidence for ofatumumab (1.50, 0.87 to 2.59); very low-certainty evidence for methotrexate (0.94, 0.02 to 46.70), corticosteroids (1.05, 0.16 to 7.14), ozanimod (1.06, 0.58 to 1.93), natalizumab (1.20, 0.77 to 1.85), ocrelizumab (1.32, 0.81 to 2.14), dimethyl fumarate (1.34, 0.96 to 1.86), siponimod (1.63, 0.96 to 2.79), rituximab (1.63, 0.53 to 5.00), cladribine (1.80, 0.89 to 3.62), mitoxantrone (2.11, 0.50 to 8.87), interferons (3.47, 0.95 to 12.72), and cyclophosphamide (3.86, 0.45 to 33.50). Eleven drugs may have increased withdrawals due to adverse events compared with placebo: low-certainty evidence for teriflunomide (1.37, 1.01 to 1.85), glatiramer acetate (1.76, 1.36 to 2.26), fingolimod (1.79, 1.40 to 2.28), interferon beta-1a (Rebif) (2.15, 1.58 to 2.93), daclizumab (2.19, 1.31 to 3.65) and interferon beta-1b (2.59, 1.87 to 3.77); very low-certainty evidence for laquinimod (1.42, 1.01 to 2.00), interferon beta-1a (Avonex) (1.54, 1.13 to 2.10), immunoglobulins (1.87, 1.01 to 3.45), peg-interferon beta-1a (3.46, 1.44 to 8.33) and azathioprine (6.95, 2.57 to 18.78); however, very low-certainty evidence is unreliable. Sensitivity analyses including only studies with low attrition bias, drug dose above the group median, or only patients with relapsing remitting MS or CIS, and subgroup analyses by prior disease-modifying treatments did not change these figures. Rankings No drug yielded consistent P scores in the upper quartile of the probability of being better than others for primary and secondary outcomes.
AUTHORS' CONCLUSIONS
We found mostly low and very low-certainty evidence that drugs used to treat MS may not increase SAEs, but may increase withdrawals compared with placebo. The results suggest that there is no important difference in the occurrence of SAEs between first- and second-line drugs and between oral, injectable, or infused drugs, compared with placebo. Our review, along with other work in the literature, confirms poor-quality reporting of adverse events from RCTs of interventions. At the least, future studies should follow the CONSORT recommendations about reporting harm-related issues. To address adverse effects, future systematic reviews should also include non-randomized studies.
Topics: Male; Female; Young Adult; Humans; Adolescent; Adult; Interferon beta-1a; Immunosuppressive Agents; Glatiramer Acetate; Network Meta-Analysis; Cladribine; Natalizumab; Interferon beta-1b; Alemtuzumab; Dimethyl Fumarate; Daclizumab; Azathioprine; Rituximab; Fingolimod Hydrochloride; Multiple Sclerosis; Immunotherapy
PubMed: 38032059
DOI: 10.1002/14651858.CD012186.pub2 -
The Cochrane Database of Systematic... Jan 2024Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015.
OBJECTIVES
To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS.
SEARCH METHODS
CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS.
DATA COLLECTION AND ANALYSIS
Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach.
MAIN RESULTS
We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.
Topics: Adult; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Glatiramer Acetate; Interferon beta-1a; Fingolimod Hydrochloride; Natalizumab; Interferon beta-1b; Cladribine; Alemtuzumab; Dimethyl Fumarate; Daclizumab; Network Meta-Analysis; Immunologic Factors; Recurrence
PubMed: 38174776
DOI: 10.1002/14651858.CD011381.pub3 -
Multiple Sclerosis and Related Disorders Jul 2023Alemtuzumab is a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), but in recent years safety-related concerns had emerged due to description... (Observational Study)
Observational Study
BACKGROUND
Alemtuzumab is a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), but in recent years safety-related concerns had emerged due to description of novel serious side effects not registered in CARE-MS I and CARE-MS II phase 3 studies, nor in TOPAZ extension study. Data about alemtuzumab use in real clinical practice are limited and based mainly on retrospective studies with small sample sizes. Therefore, more information about effectiveness and safety of alemtuzumab in this context is needed.
METHODS
A multicenter observational prospective study to investigate effectivity and safety of alemtuzumab in a real-world setting was performed. Primary endpoints were the change in annualized relapse rate (ARR), and in disability measured by EDSS score. Secondary endpoints were the cumulative probability of confirmed 6-month disability improvement and worsening. Disability worsening and disability improvement were considered when the EDSS score was increased or decreased, respectively, in 1 point if baseline EDSS score was <5.0, or in 0.5 point if baseline EDSS score was ≥5.5, confirmed over 6 months. Other secondary endpoint was the proportion of patients who achieved NEDA-3 status (absence of clinical relapses, disability EDSS progression, and MRI disease activity as depicted by new/enlarging T2 lesions or Gadolinium enhancing T1 lesions). Adverse events also were recorded.
RESULTS
A total of 195 RRMS patients (70% female) who started alemtuzumab treatment were included. Mean of follow-up was 2.38 years. Alemtuzumab significantly reduced the annualized relapse rate from baseline with risk reductions of 86%, 83.5%, and 84%, at 12, 24, and 36 months of follow-up respectively (Friedman test, p-value < 0.05 for all comparisons). Alemtuzumab also significantly reduced EDSS score over one and two years after starting alemtuzumab treatment (Friedman test, p-value<0.001 for both comparisons). A high proportion of patients presented confirmed 6-month stability or disability improvement (92%, 82%, and 79%, over 1, 2 and 3 years of follow-up respectively). The proportion of patients who retained NEDA-3 status at 12, 24 and 36 months were 61%, 49%, and 42%, respectively. Baseline characteristics associated with a lower probability of achieving NEDA-3 were younger age, sex female, high ARR, elevated number of previous treatments, and switch from a second line therapy. Infusion related reactions were the most frequent adverse event observed. The most common infections were urinary tract infections (50%), and upper respiratory tract infections (19%) over the 3 years of follow- up. Secondary thyroid autoimmunity was developed in 18.5% of patients.
CONCLUSION
Alemtuzumab has demonstrated in real clinical practice high effectiveness in controlling multiple sclerosis activity, and no unexpected adverse events were observed.
Topics: Humans; Female; Male; Alemtuzumab; Retrospective Studies; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Recurrence
PubMed: 37229800
DOI: 10.1016/j.msard.2023.104762 -
Current Neurology and Neuroscience... Sep 2023Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly considered a treatment option for patients with multiple sclerosis (MS), an autoimmune... (Review)
Review
PURPOSE OF REVIEW
Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly considered a treatment option for patients with multiple sclerosis (MS), an autoimmune demyelinating and degenerative disease of the central nervous system (CNS). AHSCT persistently suppresses inflammation and improves the disease course in large proportions of patients with relapsing-remitting (RR) MS. Aim of this article is to review the relevant new knowledge published during the last 3 years.
RECENT FINDINGS
Laboratory studies reported confirmatory and new insights into the immunological and biomarker effects of AHSCT. Retrospective clinical studies confirmed excellent outcomes in RRMS, showing possible superior effectiveness over standard therapies and suggesting a possible benefit in early secondary progressive (SP) MS with inflammatory features. New data on risks of infertility and secondary autoimmunity were also reported. Further evidence on the high effectiveness and acceptable safety of AHSCT strengthens its position as a clinical option for aggressive RRMS. Further research is needed to better define its role in treatment-naïve and progressive forms of MS, ideally within randomised clinical trials (RCTs).
Topics: Humans; Multiple Sclerosis; Retrospective Studies; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Hematopoietic Stem Cell Transplantation
PubMed: 37589918
DOI: 10.1007/s11910-023-01290-2 -
Therapeutic Advances in Neurological... 2023Alemtuzumab demonstrated superior efficacy subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and...
BACKGROUND AND OBJECTIVES
Alemtuzumab demonstrated superior efficacy subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants ('alemtuzumab-only') could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab ('IFN-alemtuzumab'). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5-7 years (11-13 years after alemtuzumab/IFN initiation).
METHODS
Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)].
RESULTS
43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3-13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15-0.20] and IFN-alemtuzumab (0.14; 0.11-0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent.
CONCLUSION
Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11-13 years, and most participants did not require more than one additional course.
CLINICALTRIALSGOV IDENTIFIERS
NCT00530348; NCT00548405; NCT00930553; NCT02255656.
PubMed: 37745914
DOI: 10.1177/17562864231194823 -
Frontiers in Immunology 2023Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms... (Review)
Review
Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.
Topics: Humans; Multiple Sclerosis; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Cladribine; Central Nervous System Diseases
PubMed: 38162670
DOI: 10.3389/fimmu.2023.1290666