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Neurology and Therapy Dec 2020Since 2010, 27 mixed-treatment comparisons (MTCs) of disease-modifying therapies (DMTs) for multiple sclerosis have been published. However, there has been continued... (Review)
Review
BACKGROUND
Since 2010, 27 mixed-treatment comparisons (MTCs) of disease-modifying therapies (DMTs) for multiple sclerosis have been published. However, there has been continued evolution in the field of MTCs. Additionally, limitations in methodological approach and reporting transparency, even in the most recent publications, makes interpretation and comparison of existing studies difficult.
OBJECTIVES
The objectives of this study are twofold: (1) to estimate the efficacy and safety of DMTs at European Commission-approved doses compared with placebo in adults with relapsing-remitting multiple sclerosis (RRMS) using MTC, and (2) to identify and address methodological challenges when performing MTC in RRMS, thereby creating a baseline for comparisons with future treatments.
METHODS
Searches were completed in 14 databases, including MEDLINE, Embase, CENTRAL, CDSR and DARE, from inception to June 2018 to identify published or unpublished prospective, randomised controlled trials of all European Union-approved DMTs or DMTs expected to be approved in the near future in RRMS or rapidly-evolving severe RRMS. No language or date restrictions were applied. Studies were included in the MTC if they were judged to have sufficiently similar characteristics, based on the following: patient age; proportion of male participants; Expanded Disability Status Scale (EDSS) score; duration of disease; number of relapses prior to enrolment and proportion of previously treated patients. Background information from the included studies, as well as effect size and confidence intervals (where relevant) of defined outcomes were extracted. Reporting of the MTC was consistent with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) network meta-analysis guidelines.
RESULTS
In total, 33 studies were included in the MTC. Annualised relapse rate (ARR 28 trials) was significantly reduced in all treatments compared with placebo. Alemtuzumab had the highest probability (63%) of being the most effective treatment in terms of ARR compared with placebo (rate ratio [RR] 0.28, 95% credible interval [CrI] 0.21-0.38), followed by natalizumab (30% probability; RR 0.32, 95% CrI 0.23-0.43). The risk of 3- and 6-month confirmed disability progression (CDP3M, 13 trials; CDP6M, 14 trials) were similar; CDP6M was significantly reduced for alemtuzumab (hazard ratio [HR] 0.365; 95% CrI 0.165-0.725), ocrelizumab (HR 0.405, 95% CrI 0.188-0.853) and natalizumab (HR 0.459, 95% CrI 0.252-0.840) relative to placebo. There were no significant differences in the odds of serious adverse events (SAEs, 6 trials) between any treatment and placebo. The results of the MTC were limited by the lack of studies reporting direct comparisons between the included treatments and by heterogeneous reporting of key outcome data.
CONCLUSIONS
Meta-analyses confirmed the benefit of all DMTs in terms of relapse rate compared with placebo with a comparable rate of SAEs for the DMTs that could be included in the network. The rigor and transparency of reporting in this study provide a benchmark for comparisons with future new agents.
PubMed: 32989721
DOI: 10.1007/s40120-020-00212-5 -
Farmacia Hospitalaria : Organo Oficial... Mar 2020To identify and describe cost-effectiveness studies that evaluate disease modifying therapies in the context of relapsing- remitting multiple sclerosis. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To identify and describe cost-effectiveness studies that evaluate disease modifying therapies in the context of relapsing- remitting multiple sclerosis.
METHOD
A systematic review of the literature was carried out by searching MEDLINE, Embase, the Cochrane Library, LILACS, the Tufts Medical Center Cost-Effectiveness Analysis Registry, the National Health Service Economic Evaluation Database and Open Grey. The search was performed in January 2018 and covered articles published between January 2010 and December 2017. The studies reviewed were payer- perspective cost-effectiveness analyses for interferon beta-1a, interferon beta-1b, glatiramer acetate, teriflunomide, fingolimod, dimethyl fumarate, natalizumab, alemtuzumab and rituximab. The Quality of Health Economic Studies instrument was used to determine the quality of the studies reviewed. Risk of bias was assessed without a standardized tool. An analysis was made of direct costs, quality- adjusted life-years and the incremental cost-effectiveness ratio. Data extraction and evaluation of information were conducted separately by each author.
RESULTS
Four hundred one references were found; nine studies were included. A great degree of variability was identified for several methodological aspects. Two studies that applied the incremental cost- effectiveness ratio (cost) showed no first-line therapy to be cost- effective. A third study demonstrated dominance of interferon beta-1b over placebo (USD -315,109.45) and a fourth paper showed dominance of teriflunomide over interferons and glatiramer acetate (USD - 121,840.37). As regards second-line therapies, dimethyl fumarate was cost-effective in a study that compared it to glatiramer acetate and interferon beta-1a and it was dominant in another study that compared it with glatiramer acetate (USD -158,897.93) and fingolimod (USD - 92,988.97). In the third line of treatment, one study showed natalizumab to be cost-effective as compared with fingolimod, and another study showed alemtuzumab to be dominant over fingolimod (USD -49,221). A third trial demonstrated alemtuzumab to be dominant over natalizumab (USD -1,656,266.07). Many of the trials have sponsorship bias. Eight of the trials received a high QHES score.
CONCLUSIONS
The present paper shows that cost-effectiveness studies have high levels of methodological variability, some of them reaching contradictory results. As a result, it is not possible to determine which disease- modifying therapy is really cost-effective in the context of relapsingremitting multiple sclerosis.
Topics: Antibodies, Monoclonal; Antirheumatic Agents; Cost-Benefit Analysis; Humans; Immunosuppressive Agents; Multiple Sclerosis, Chronic Progressive; Quality-Adjusted Life Years
PubMed: 32452318
DOI: 10.7399/fh.11385 -
Autoimmunity Reviews Apr 2020Immune reconstitution therapy (IRT) is an emerging concept for the treatment of multiple sclerosis (MS) that is given intermittently and can induce long-term remission...
Immune reconstitution therapy (IRT) is an emerging concept for the treatment of multiple sclerosis (MS) that is given intermittently and can induce long-term remission of MS that is sustained in treatment-free periods. A systematic literature review was performed to identify and summarize current knowledge regarding the short- and long-term immunological consequences of different IRTs and CD20 depleting therapies on the cellular level in patients with MS. A total of 586 articles published between January 2010 and September 2019 were identified and screened; 44 studies met inclusion criteria for the review. All the treatments considered appeared to produce both qualitative and quantitative changes in the immune cell populations of patients with MS that resulted in a more anti-inflammatory immune profile. Autologous hematopoietic stem cell transplantation produced the longest-lasting and greatest effects on a wide range of immune cells. Many patients achieved prolonged depletion of the adaptive immune system when alemtuzumab and cladribine tablets were administered as short courses of therapy; however, a proportion of patients required retreatment to maintain these effects. Alemtuzumab may produce greater depletion of both CD4+ and CD8+ T cells than cladribine tablets, although both treatments similarly deplete B cells. Recovery of B cells before T cell recovery and hyperpopulation of B cells after alemtuzumab may contribute to secondary autoimmunity. Cladribine tablets had a greater effect on B cells than T cells, and no hyperpopulation of B cells was observed after treatment with cladribine tablets. Ocrelizumab and rituximab require regular repeated treatment every 6 months to maintain depletion of B and T cells. Effects of the drug treatments on the innate immune system were minor compared with those on the adaptive immune system. Additional characterization of the cellular changes occurring during IRT and CD20 depletion may lead to further improvement in the understanding of the pathogenesis of MS and the future development of therapies with even longer lasting effects. Although the treatments considered in this review improve quality of life and outcomes for patients with MS, a cure for this debilitating disease is not yet in sight.
Topics: Alemtuzumab; Autografts; Cladribine; Hematopoietic Stem Cell Transplantation; Humans; Immune Reconstitution; Multiple Sclerosis; Quality of Life
PubMed: 32062028
DOI: 10.1016/j.autrev.2020.102492 -
Current Hematologic Malignancy Reports Apr 2020T cell prolymphocytic leukemia (T-PLL) is a rare mature T cell tumor. Available treatment options in this aggressive disease are largely inefficient and patient outcomes...
PURPOSE OF REVIEW
T cell prolymphocytic leukemia (T-PLL) is a rare mature T cell tumor. Available treatment options in this aggressive disease are largely inefficient and patient outcomes are highly dissatisfactory. Current therapeutic strategies mainly employ the CD52-antibody alemtuzumab as the most active single agent. However, sustained remissions after sole alemtuzumab-based induction are exceptions. Responses after available second-line strategies are even less durable. More profound disease control or rare curative outcomes can currently only be expected after a consolidating allogeneic hematopoietic stem cell transplantation (allo-HSCT) in best first response. However, only 30-50% of patients are eligible for this procedure. Major advances in the molecular characterization of T-PLL during recent years have stimulated translational studies on potential vulnerabilities of the T-PLL cell. We summarize here the current state of "classical" treatments and critically appraise novel (pre)clinical strategies.
RECENT FINDINGS
Alemtuzumab-induced first remissions, accomplished in ≈ 90% of patients, last at median ≈ 12 months. Series on allo-HSCT in T-PLL, although of very heterogeneous character, suggest a slight improvement in outcomes among transplanted patients within the past decade. Dual-action nucleosides such as bendamustine or cladribine show moderate clinical activity as single agents in the setting of relapsed or refractory disease. Induction of apoptosis via reactivation of p53 (e.g., by inhibitors of HDAC or MDM2) and targeting of its downstream pathways (i.e., BCL2 family antagonists, CDK inhibitors) are promising new approaches. Novel strategies also focus on inhibition of the JAK/STAT pathway with the first clinical data. Implementations of immune-checkpoint blockades or CAR-T cell therapy are at the stage of pre-clinical assessments of activity and feasibility. The recommended treatment strategy in T-PLL remains a successful induction by infusional alemtuzumab followed by a consolidating allo-HSCT in eligible patients. Nevertheless, long-term survivors after this "standard" comprise only 10-20%. The increasingly revealed molecular make-up of T-PLL and the tremendous expansion of approved targeted compounds in oncology represent a "never-before" opportunity to successfully tackle the voids in T-PLL. Approaches, e.g., those reinstating deficient cell death execution, show encouraging pre-clinical and first-in-human results in T-PLL, and urgently have to be transferred to systematic clinical testing.
Topics: Alemtuzumab; Animals; Antineoplastic Agents, Immunological; Diffusion of Innovation; Forecasting; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Leukemia, Prolymphocytic, T-Cell; Molecular Targeted Therapy; Receptors, Chimeric Antigen; Treatment Outcome
PubMed: 32034661
DOI: 10.1007/s11899-020-00566-5 -
Expert Review of Hematology Apr 2020: To summarize the impact of relapsed/refractory primary cutaneous T-cell lymphomas (CTCL) on quality of life (QoL) and the efficacy of available treatments in two...
: To summarize the impact of relapsed/refractory primary cutaneous T-cell lymphomas (CTCL) on quality of life (QoL) and the efficacy of available treatments in two systematic reviews (SRs).: Searches were performed on 16 January 2018 and 23 January 2018, respectively, in Medline, Medline in process, the Cochrane database, and EconLit. Studies reporting QoL outcomes in adults with CTCL or treatment efficacy in relapsed/refractory CTCL were included.: Based on 15 QoL studies, CTCL symptoms/complications negatively affect patients' physical, emotional, and social functioning. Skin problems pose considerable symptom burden, while advanced disease stage is associated with poorer QoL. CTCL negatively affects caregivers, primarily through family dynamics and relationships. The clinical efficacy SR included 72 publications covering 23 therapies. Overall response rate (ORR) ranged from 14% (belinostat) to 95% (total skin electron beam therapy). ORRs >50% were reported for several therapies including brentuximab vedotin (50-78%) and bexarotene (39-86%). Over half (13 of 23 therapies) had ORRs <30%. Median progression-free survival varied between treatments (3.5-116.4 months) and was >20 months for brentuximab vedotin and alemtuzumab.: CTCL negatively affects patients' and caregivers' QoL. A considerable proportion of patients have no response or no sustainable response to current treatments.
Topics: Antineoplastic Agents; Cost of Illness; Disease-Free Survival; Humans; Lymphoma, T-Cell, Cutaneous; Quality of Life; Skin Neoplasms; Survival Rate
PubMed: 31958235
DOI: 10.1080/17474086.2020.1717945 -
Journal of Endocrinological... Feb 2020Autoimmune thyroid events (ATEs) are common side effects after alemtuzumab (ALZ) therapy in patients with multiple sclerosis (MS). Our purpose was to reach more robust... (Meta-Analysis)
Meta-Analysis
PURPOSE
Autoimmune thyroid events (ATEs) are common side effects after alemtuzumab (ALZ) therapy in patients with multiple sclerosis (MS). Our purpose was to reach more robust evidence on prevalence and outcome of the spectrum of alemtuzumab-induced autoimmune thyroid events in patients with multiple sclerosis.
METHODS
PubMed and Scopus were systematically searched through July 2019. Studies dealing with patients without personal history of thyroid dysfunctions and affected by MS treated with ALZ and reporting ATEs were selected. Data on prevalence and outcome of ATEs were extracted. A proportion of meta-analysis with random-effects model was performed.
RESULTS
Considering the overall pooled number of 1362 MS patients treated with ALZ (seven included studies), a 33% prevalence of newly diagnosed ATEs was recorded. Among all ATEs, Graves' disease (GD) was the most represented [63% of cases, 95% confidence interval (CI) 52-74%], followed by Hashimoto thyroiditis (15%, 95% CI 10-22%). Interestingly, GD showed a fluctuating course in 15% of cases (95% CI 8-25%). Of all GD, 12% (95% CI 2-42%) likely had spontaneous remission, 56% (95% CI 34-76%) required only antithyroid drugs, 22% (95% CI 13-32%) needed additional RAI, and 11% (95% CI 0.9-29%) underwent definitive surgery.
CONCLUSION
Among different categories of ATEs, Graves' hyperthyroidism was the most common thyroid dysfunction, occurring in more than half of cases. Antithyroid drugs should represent the first-line treatment for ALZ-induced GD patients. However, alemtuzumab-induced GD could not be considered as having a more favourable outcome than conventional GD, given the substantial chance to encounter a fluctuating and unpredictable course.
Topics: Alemtuzumab; Antineoplastic Agents, Immunological; Antithyroid Agents; Humans; Multiple Sclerosis; Observational Studies as Topic; Randomized Controlled Trials as Topic; Thyroid Diseases
PubMed: 31452116
DOI: 10.1007/s40618-019-01105-7 -
BMC Research Notes Aug 2019Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized...
OBJECTIVE
Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized European Medicines Agency database of suspected adverse reactions related to medicinal products (EudraVigilance) for fatal adverse events associated with treatment with alemtuzumab (Lemtrada®) for multiple sclerosis. Four independent reviewers with expertise on MS, clinical immunology, infectious diseases and clinical pharmacology reviewed the reports, and scored the likelihood for causality.
RESULTS
We identified nine cases with a probable and one case with a possible causal relationship between alemtuzumab treatment and a fatal adverse event. Six of these patients died within one month after treatment; one from intracerebral hemorrhage, two from acute multiple organ failure and septic shock, one from listeriosis, one from pneumonia and one from agranulocytosis. Four patients died several months after administration of alemtuzumab from either autoimmune hepatitis, immune-mediated thrombocytopenia, autoimmune hemolytic anemia or agranulocytosis. Four of the 10 cases had been published previously in case reports or congress abstracts. Fatal adverse events related to treatment with alemtuzumab occur more frequently than previously published in the literature. A significant proportion occurs in the first month after treatment.
Topics: Adult; Agranulocytosis; Alemtuzumab; Cerebral Hemorrhage; Fatal Outcome; Female; Humans; Immunologic Factors; Listeriosis; Male; Middle Aged; Multiple Organ Failure; Multiple Sclerosis, Relapsing-Remitting; Pneumonia
PubMed: 31405369
DOI: 10.1186/s13104-019-4507-6 -
Journal of Neurology Dec 2020Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. The treatment of MS has always been a focus of neurological research. To... (Meta-Analysis)
Meta-Analysis Review
Comparative efficacy and acceptability of disease-modifying therapies in patients with relapsing-remitting multiple sclerosis: a systematic review and network meta-analysis.
BACKGROUND
Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. The treatment of MS has always been a focus of neurological research. To date, the US Food and Drug Administration has approved 15 medications for modifying the course of multiple sclerosis. In this study, we examined the effects of disease-modifying therapies (DMTs) on clinical outcomes.
METHODS
We did a systematic review and network meta-analysis based on randomized controlled trials (RCTs) comparing DMTs in patients with relapsing-remitting multiple sclerosis (RRMS). We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for RCTs published up to Oct 31, 2018. The primary outcome was efficacy (relapse rate over 24 months) and acceptability (treatment discontinuation due to adverse events over 24 months).
FINDINGS
We identified 23 suitable trials encompassing 14,096 participants. During the 2 years of follow-up, all drugs were significantly more effective than were placebos. The risk ratios with 95% credible intervals were as follows: alemtuzumab, 0.49 (0.40, 0.59); ocrelizumab, 0.49 (0.40, 0.61); mitoxantrone, 0.47 (0.27, 0.80); natalizumab, 0.51 (0.43, 0.61); fingolimod, 0.57 (0.50, 0.65); peginterferon beta-1a, 0.63 (0.52, 0.77); dimethyl fumarate, 0.65 (0.56, 0.74); teriflunomide 14 mg, 0.78 (0.66, 0.92); glatiramer acetate, 0.80 (0.72, 0.89); IFN β-1a (Rebif), 0.81 (0.72, 0.90); IFN β-1b (Betaseron), 0.81 (0.72, 0.91); teriflunomide 7 mg, 0.83 (0.71, 0.98); and IFN β-1a (Avonex). 0.87 (0.77, 0.99). Risk ratios compared with placebo for discontinuation due to adverse events ranged from 1.12 for the best drug (fingolimod) to 0.10 for the worst drug (mitoxantrone); from 0.24 (alemtuzumab) to 0.89 (IFNβ-1b [Betaseron]) for sustained (3-month) disability progression; and from 0.85 (natalizumab) to 1.25 (teriflunomide 14 mg) for the number of participants with serious adverse events.
INTERPRETATION
All DMTs were superior to placebo in reducing the relapse rate during the 2 years of follow-up. As to the comparison between drugs, alemtuzumab, ocrelizumab, natalizumab and fingolimod had a relatively higher response and lower dropout rates than did the other DMTs.
Topics: Fingolimod Hydrochloride; Glatiramer Acetate; Humans; Immunosuppressive Agents; Interferon beta-1a; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Network Meta-Analysis
PubMed: 31129710
DOI: 10.1007/s00415-019-09395-w -
Current Medical Research and Opinion Aug 2019To estimate the comparative efficacy of cladribine tablets versus alternative disease modifying therapies (DMTs) - fingolimod, natalizumab, alemtuzumab and ocrelizumab... (Meta-Analysis)
Meta-Analysis
Estimating the comparative efficacy of cladribine tablets versus alternative disease modifying treatments in active relapsing-remitting multiple sclerosis: adjusting for patient characteristics using meta-regression and matching-adjusted indirect treatment comparison approaches.
To estimate the comparative efficacy of cladribine tablets versus alternative disease modifying therapies (DMTs) - fingolimod, natalizumab, alemtuzumab and ocrelizumab - in adults with active relapsing-remitting multiple sclerosis (RRMS), using meta-regression to provide subpopulation-specific estimates of drug effect. Additionally, to determine the feasibility of conducting a matching-adjusted indirect comparison (MAIC) to validate the meta-regression results. A published systematic literature review (SLR) identified studies evaluating the efficacy of cladribine tablets and alternative DMTs in the management of active RRMS. A series of meta-regression models were run with adjustment for baseline risk, fitted to data from the intention-to-treat cohorts of trials identified in the SLR. A non-parametric MAIC analysis adjusted for differences between studies by reweighting patient-level data from the index trial to match the mean baseline characteristics reported for trials with only aggregate data. The meta-regression analysis showed significant overlap in credible intervals for the hazard ratios of 6 month confirmed disability progression (CDP-6M) and annualized relapse rate (ARR), with no therapy statistically dominating in terms of efficacy and all therapies estimated to reduce the ARR compared to placebo in all subpopulations. In the MAIC analysis, cladribine tablets showed a reduction in CDP-6M and ARR comparable to alemtuzumab before and after matching. This analysis has demonstrated that cladribine tablets have comparable relative efficacy to other highly efficacious DMTs in active RRMS across all subpopulations, thus validating the comparative effectiveness results from previous network meta-analysis. The MAIC analysis showed that cladribine tablets are comparable in efficacy to alemtuzumab in the treatment of patients with RRMS.
Topics: Cladribine; Disease Progression; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Tablets; Treatment Outcome
PubMed: 30786783
DOI: 10.1080/03007995.2019.1585779 -
European Journal of Dermatology : EJD Dec 2018The efficacy of alemtuzumab for the treatment of refractory Sézary syndrome (SS) versus other third-line agents such as pralatrexate and gemcitabine is poorly... (Comparative Study)
Comparative Study
The efficacy of alemtuzumab for the treatment of refractory Sézary syndrome (SS) versus other third-line agents such as pralatrexate and gemcitabine is poorly characterized. To elucidate the effectiveness of alemtuzumab versus other third-line options for the treatment of refractory SS, we conducted a meta-analysis of existing data. A systematic review was performed in March 2017 based on a search using Ovid-MEDLINE and OVID-EMBASE for articles evaluating single-agent alemtuzumab, gemcitabine, or pralatrexate for the treatment of SS and mycosis fungoides (MF). Twenty-two publications were identified that fulfilled all search criteria (total n = 323 patients), with six publications of lower quality being excluded from our analysis in order to decrease the risk of bias (final: n = 308 patients; 93 with SS and 147 with MF). Across all studies, alemtuzumab was significantly more effective in patients with SS (overall response rate [ORR]: 81%; complete response rate [CRR]: 38%) than patients with MF (ORR: 29%; CRR: 8%). However, gemcitabine was more effective than alemtuzumab or pralatrexate in treating MF. Alemtuzumab-treated patients had more frequent side effects, which were influenced by route of administration and dose. There was a lower incidence of lymphopenia and other serious adverse events in patients treated with subcutaneous (38%) compared to intravenous regimens (68%), and lower-dose (5%) compared to high-dose alemtuzumab regimens (54%). No significant differences were found in the effectiveness of different routes of administration or dosing regimens. Our review supports the use of low-dose subcutaneous alemtuzumab as a third-line treatment for SS.
Topics: Alemtuzumab; Aminopterin; Antimetabolites, Antineoplastic; Antineoplastic Agents, Immunological; Deoxycytidine; Folic Acid Antagonists; Humans; Mycosis Fungoides; Retreatment; Sezary Syndrome; Skin Neoplasms; Gemcitabine
PubMed: 30591425
DOI: 10.1684/ejd.2018.3444