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Journal of Neuroimmunology Nov 2021Background High efficacy disease modifying therapies (DMT) in the management of Multiple Sclerosis (MS) have a favorable effect on relapse rate and disability... (Meta-Analysis)
Meta-Analysis
Background High efficacy disease modifying therapies (DMT) in the management of Multiple Sclerosis (MS) have a favorable effect on relapse rate and disability progression; however, they can expose patients to significant risks, such as progressive multifocal leukoencephalopathy (PML). Objective The study aims to investigate prognostic factors that can determine outcome in MS-related PML patients. Methods We conducted a literature review and meta-analysis of 194 patients from 62 articles in PubMed, SCOPUS and EMBASE. Results Out of 194 patients (66.5% women, 33.5% men), 81% had progression in their EDSS score by at least 1 point from the time of PML diagnosis (EDSS-P group). The remaining patients had either stable or improved EDSS (EDSS-S group). In univariate analysis, older age at the time of PML diagnosis was associated with higher probability of disability accumulation and worsening of EDSS by at least 1 point (mean age = 44.8, p = 0.046). After adjusting for other variables, age at time of PML diagnosis remained a significant predictive variable in the multivariable logistic model (OR = 0.93, 95% CI: 0.88-0.99, p = 0.037). Natalizumab is the most commonly associated DMT linked to PML, followed by fingolimod and others including dimethyl fumarate, ocrelizumab, alemtuzumab. Among the different treatments used, no therapeutic agent was found to be superior in improving post-PML EDSS. Conclusions Younger age and lower JCV viral load at the time of PML diagnosis were associated with better outcome in MS-associate PML, while none of the PML therapies was superior over the others or associated with favorable outcome.
Topics: Age Factors; Antirheumatic Agents; Cerebrospinal Fluid; Disability Evaluation; Disease Progression; Endemic Diseases; Female; Humans; Immunocompromised Host; JC Virus; Leukoencephalopathy, Progressive Multifocal; Male; Multiple Sclerosis; Natalizumab; Prognosis; Severity of Illness Index; Viral Load
PubMed: 34547511
DOI: 10.1016/j.jneuroim.2021.577721 -
Vaccines Jul 2021Understanding the risks of COVID-19 in patients with Multiple Sclerosis (MS) receiving disease-modifying therapies (DMTs) and their immune reactions is vital to analyze... (Review)
Review
Understanding the risks of COVID-19 in patients with Multiple Sclerosis (MS) receiving disease-modifying therapies (DMTs) and their immune reactions is vital to analyze vaccine response dynamics. A systematic review on COVID-19 course and outcomes in patients receiving different DMTs was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Emerging data on SARS-CoV-2 vaccines was used to elaborate recommendations. Data from 4417 patients suggest that MS per se do not portend a higher risk of severe COVID-19. As for the general population, advanced age, comorbidities, and higher disability significantly impact COVID-19 outcomes. Most DMTs have a negligible influence on COVID-19 incidence and outcome, while for those causing severe lymphopenia and hypogammaglobulinemia, such as anti-CD20 therapies, there might be a tendency of increased hospitalization, worse outcomes and a higher risk of re-infection. Blunted immune responses have been reported for many DMTs, with vaccination implications. Clinical evidence does not support an increased risk of MS relapse or vaccination failure, but vaccination timing needs to be individually tailored. For cladribine and alemtuzumab, it is recommended to wait 3-6 months after the last cycle until vaccination. For the general anti-CD20 therapies, vaccination must be deferred toward the end of the cycle and the next dose administered at least 4-6 weeks after completing vaccination. Serological status after vaccination is highly encouraged. Growing clinical evidence and continuous surveillance are extremely important to continue guiding future treatment strategies and vaccination protocols.
PubMed: 34358189
DOI: 10.3390/vaccines9070773 -
Expert Opinion on Drug Safety Oct 2021We aimed to systematically assess the pooled prevalence of infective complications in randomized controlled trials (RCTs) and real-world studies (RWSs) investigating... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
We aimed to systematically assess the pooled prevalence of infective complications in randomized controlled trials (RCTs) and real-world studies (RWSs) investigating alemtuzumab treatment in multiple sclerosis (MS), also looking at selected infections and their severity.
METHODS
We included in the analysis RCTs and RWSs investigating the use of alemtuzumab in MS in which infective complications were reported, as well as case reports of rare infections. We conducted a meta-analysis of proportions and a random effect model meta-regression to investigate heterogeneity.
RESULTS
The pooled prevalence of infective complications in alemtuzumab treated MS patients is 24%. The most common reported infections are respiratory tract infections (47%) and the most part of the infections are mild-to-moderate (85%). Severe infections account for 6% of the total estimate. We found first-time-reported cases of invasive aspergillosis, hepatitis E virus infection, EBV hepatitis, and cerebral toxoplasmosis. The prevalence of infections is higher in studies conducted before 2009, and in studies with higher proportion of male participants.
CONCLUSIONS
Clinicians should be aware that the prevalence of serious infections during alemtuzumab can be higher than expected from RCTs. Peculiar opportunistic infections should be considered when evaluating a patient treated with alemtuzumab who develops signs of infection.
Topics: Alemtuzumab; Humans; Immunologic Factors; Multiple Sclerosis; Opportunistic Infections; Prevalence; Randomized Controlled Trials as Topic; Severity of Illness Index
PubMed: 34310251
DOI: 10.1080/14740338.2021.1942454 -
British Journal of Haematology Dec 2021Lymphocyte-variant hypereosinophilic syndrome (L-HES) is a rare disease driven by immunophenotypically aberrant T cells producing eosinophilopoetic cytokines such as...
Lymphocyte-variant hypereosinophilic syndrome (L-HES) is a rare disease driven by immunophenotypically aberrant T cells producing eosinophilopoetic cytokines such as interleukin-5 (IL-5). Treatment is challenging because L-HES is relatively steroid resistant and not amenable to tyrosine kinase inhibitors. We searched the literature for clinical trials and observational studies, including case reports, of patients treated for L-HES. In all, 25 studies were selected; two were randomised controlled trials of IL-5 blockade, which included some patients with L-HES, and the rest were observational studies. Corticosteroids are often used as first-line therapy, but patients with L-HES have lower response rates than other types of HES. Treatments that reduce symptoms and steroid dependence in some patients include interferon-alpha (IFN-α), anti-IL-5 monoclonal antibodies, cyclosporine and mycophenolate. These drugs target T-cell activation and proliferation, or IL-5 directly. Although effective, IFN-α and cyclosporine were commonly reported to cause side-effects resulting in discontinuation. Alemtuzumab can induce remissions, but these are generally short lived. The anti-IL-5 monoclonal antibodies mepolizumab and benralizumab are effective and well tolerated, but with a high rate of relapse once withdrawn. Hydroxyurea, methotrexate, imatinib were unsuccessful in most patients studied. More prospective clinical trials are needed for patients with L-HES.
Topics: Adrenal Cortex Hormones; Alemtuzumab; Antibodies, Monoclonal; Cyclosporine; Humans; Hydroxyurea; Hypereosinophilic Syndrome; Imatinib Mesylate; Immunologic Factors; Immunosuppressive Agents; Interferon-alpha; Interleukin-5; Lymphocyte Activation; Lymphocytes
PubMed: 34105142
DOI: 10.1111/bjh.17615 -
Experimental and Clinical... May 2021Induction immunosuppression for simultaneous pancreas-kidney transplant has helped reduce graft loss due to early rejection. Both thymoglobulin and interleukin 2... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Induction immunosuppression for simultaneous pancreas-kidney transplant has helped reduce graft loss due to early rejection. Both thymoglobulin and interleukin 2 receptor antagonists are the most commonly used induction agents; however, some high-volume centers prefer alemtuzumab.Thisnetwork meta-analysis aimedto compare differentinductionregimens for simultaneouspancreaskidney transplantin terms ofbothpancreas and patient graft survival, as well to assess acute rejection.
MATERIALS AND METHODS
A systematic review was conducted to identify randomized clinical trials up to October 31, 2019, that examined induction regimens for simultaneous pancreas-kidney transplant. Study characteristics, postoperative data (patient, pancreas, and kidney graft survival), complications (eg, bleeding), infection rates, and malignancy rates were extracted. We compared all regimens using randomeffects network meta-analyses to maintain randomization within trials.
RESULTS
This study identified 7 randomized clinical trials that involved 536 patients, which reported 5 induction regimens. These regimens included antithymocyte globulin (97 patients), alemtuzumab (42 patients), 2 doses (113 patients) or 5 doses (164 patients) of daclizumab, and no induction therapy (120 patients). In the network meta-analysis, a regimen with 2 doses of daclizumab was consistently ranked first for patient survival and kidney and pancreas graft survival. In contrast, alemtuzumab was ranked best for acute rejection (both pancreas and kidney). Rates of majorinfection (ie, cytomegalovirus) and malignancy were reported in 3 studies, precluding a reliable analysis.
CONCLUSIONS
Daclizumab with 2 doses, given before simultaneous pancreas-kidney transplant, was associated with the best rates of patient and graft survival. Despite the recent withdrawal of daclizumab, an alternative anti-interleukin 2 induction regimen (basiliximab) has demonstrated promising results in nonrandomized series, warranting that further highquality large-scale randomized clinical trials are still needed.
Topics: Alemtuzumab; Daclizumab; Humans; Immunosuppression Therapy; Kidney Transplantation; Neoplasms; Network Meta-Analysis; Pancreas Transplantation; Randomized Controlled Trials as Topic
PubMed: 34053419
DOI: 10.6002/ect.2020.0231 -
Journal Der Deutschen Dermatologischen... Aug 2021Alemtuzumab is currently approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). Despite the efficacy of this therapy several side effects in... (Review)
Review
Alemtuzumab is currently approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). Despite the efficacy of this therapy several side effects in the skin have been noted during or after infusion including vitiligo, alopecia areata, malignant skin tumors and infections. Awareness of these effects and their treatment is of essential interdisciplinary importance. This minireview provides an overview of the dermatological side effects described in the current literature. We also suggest pathomechanisms underlying these phenomena. To introduce this review, we present the case of a woman with RRMS who developed severe alopecia areata for the first time on alemtuzumab.
Topics: Alemtuzumab; Alopecia Areata; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Multiple Sclerosis, Relapsing-Remitting; Vitiligo
PubMed: 33973347
DOI: 10.1111/ddg.14448 -
Expert Review of Pharmacoeconomics &... Oct 2021: Novel immunotherapeutic agents (e.g. monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engagers) as treatment options for hematologic malignancies...
: Novel immunotherapeutic agents (e.g. monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engagers) as treatment options for hematologic malignancies continue to emerge. These agents have been used as the standard of care in specific disease states and are associated with high costs. Value assessment of these therapies is of critical importance for coverage and reimbursement decision-making.: We identified 15 immunotherapeutic agents through the U.S. FDA approvals for hematologic malignancies until 2018 and systematically reviewed related cost-effectiveness studies. Additionally, we examined whether drug wastage was accounted for in these studies.: We reviewed 51 studies for 14 identified immunotherapeutic agents that met the inclusion criteria for this systematic review. Three studies were observational-based, one study was model-based and incorporated observational data. The remaining studies were model-based with the majority of the model parameters extracted from randomized control trials (RCTs). Among 43 model-based economic evaluations, 13 studies accounted for drug wastage. Most of the studies showed favorable incremental cost-effectiveness ratios of immunotherapeutic agents-containing regimens when compared with no immunotherapeutic agents-containing regimens. Alemtuzumab, brentuximab vedotin, and daratumumab were not considered cost-effective across all the studies. Further investigations are warranted to establish the value of recent immunotherapeutic agents for hematologic malignancies.
Topics: Antineoplastic Agents, Immunological; Cost-Benefit Analysis; Hematologic Neoplasms; Humans; Immunotherapy; Models, Economic; Randomized Controlled Trials as Topic; Refuse Disposal
PubMed: 33934691
DOI: 10.1080/14737167.2021.1913056 -
Autoimmunity Reviews Jun 2021To compare the efficacy and compliance of up-to-date disease modifying therapies (DMTs) in patients with remitting-relapsing MS (RRMS). (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To compare the efficacy and compliance of up-to-date disease modifying therapies (DMTs) in patients with remitting-relapsing MS (RRMS).
METHODS
We searched PubMed, EMBASE and Cochrane Library for eligible studies. Annualized relapse rate, discontinuation due to adverse events (AEs) were assessed as primary outcomes. Sensitivity analysis and inconsistency detection were performed to evaluated whether exclusion of high-risk studies affected the validity. Risk of bias was assessed using Cochrane's Risk-of-Bias Tool 2. Surface under the cumulative ranking curve (SUCRA) was used to estimate the rankings among different DMTs.
RESULTS
21 studies were included for main report. Seven studies were evaluated as "high risk" and were therefore excluded. Exclusion of high-risk studies did not affect the validity of evidence. The risk of relapses for most DMTs except Betaseron 50 μg was significantly lower comparing to placebo. Incompliance in patients treated with DMTs was not significantly increased comparing to placebo. Dimethyl fumarate and ocrelizumab had superiority in improving MRI outcomes. Ocrelizumab and ofatumumab had the largest reduction of risk in disability progression at 3 months. Referring to SUCRA, ofatumumab, alemtuzumab and natalizumab showed the best efficacy and compliance.
CONCLUSION
The present study demonstrated the hierarchy of DMTs treating RRMS. Ofatumumab, alemtuzumab and natalizumab have superiority with respect to effectiveness and compliance. More studies are required to explore the long-term effect of DMTs. Our findings could provide helpful information and contribute to clinical treatment decision-making.
Topics: Humans; Immunologic Factors; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Network Meta-Analysis
PubMed: 33878488
DOI: 10.1016/j.autrev.2021.102826 -
Neurologia Mar 2021This article analyses the presence of gender bias in clinical trials of monoclonal antibodies used to treat multiple sclerosis. (Review)
Review
INTRODUCTION
This article analyses the presence of gender bias in clinical trials of monoclonal antibodies used to treat multiple sclerosis.
MATERIAL AND METHODS
We performed a systematic review of controlled clinical trials of 4 monoclonal antibodies used to treat multiple sclerosis (natalizumab, rituximab, alemtuzumab, and ocrelizumab). We searched the PubMed/MEDLINE database for articles published in English before March 2020. The study was conducted in accordance with the relevant international recommendations.
RESULTS
The search identified 89 articles, 55 of which met the inclusion criteria. Of all patients included in these trials, 64.6% were women. The lead authors of 10 of the studies were women. Fifteen of the 55 studies included a sex-based analysis of the primary endpoint. Only 8 articles discussed the results separately for men and for women.
CONCLUSIONS
The clinical trials of these 4 monoclonal antibodies present a significant gender bias. In most cases, the primary and secondary endpoints are not analyzed according to patient sex, despite the fact that international recommendations include this as a minimum requirement for ensuring scientific validity and obtaining appropriate results for extrapolation to the wider population.
PubMed: 33775476
DOI: 10.1016/j.nrl.2021.01.003 -
Clinical Therapeutics Oct 2020The goal of this study was to estimate the relative efficacy of acalabrutinib (monotherapy and in combination with obinutuzumab) compared with standard frontline... (Comparative Study)
Comparative Study Meta-Analysis
PURPOSE
The goal of this study was to estimate the relative efficacy of acalabrutinib (monotherapy and in combination with obinutuzumab) compared with standard frontline treatments for chronic lymphocytic leukemia (CLL) in fludarabine-ineligible patients, through a network meta-analysis (NMA).
METHODS
The efficacy of acalabrutinib from ELEVATE-TN (study of Obinutuzumab + Chlorambucil, Acalabrutinib [ACP-196] + Obinutuzumab, and Acalabrutinib in Subjects With Previously Untreated CLL) was compared to bendamustine + rituximab, chlorambucil-based therapy, alemtuzumab, ibrutinib mono/combination therapy and venetoclax + obinutuzumab using data from eight randomized controlled trials (RCTs). Relevant RCTs were identified using a systematic literature review. Two evidence networks were constructed: Network A, composed solely of RCTs that met the inclusion criteria; and Network B, composed of 7 RCTs and a published cross-trial comparison of ibrutinib from RESONATE-2 and chlorambucil + obinutuzumab from iLLUMINATE. Bayesian NMAs were conducted on progression-free survival (PFS) and overall survival (OS) endpoints; results were reported by using hazard ratios (HRs) and 95% credible intervals (CrIs). HRs were considered significant if their CrIs did not cross 1. Treatments were ranked by using the surface under the cumulative ranking area (SUCRA) values. Expert opinion from 2 hematologists was sought to validate results.
FINDINGS
Both networks showed a significant improvement in PFS for acalabrutinib + obinutuzumab over all comparators. Both networks also showed a significant improvement in PFS for acalabrutinib monotherapy versus most comparators, with a significant difference to ibrutinib monotherapy found in Network A but not Network B. Conversely, a significant difference in PFS was observed for acalabrutinib monotherapy versus venetoclax + obinutuzumab in Network B but not Network A. Although OS HRs all favored acalabrutinib, most were not significant and were characterized by wide CrIs, indicating a high level of uncertainty. Acalabrutinib + obinutuzumab ranked highest in terms of PFS improvement (SUCRA values, 98% and 100%) and OS improvement (SUCRA values, 92% and 94%), followed by acalabrutinib monotherapy (SUCRA values for PFS, 88% and 90%; OS, 83% and 87%) in Networks A and B, respectively.
IMPLICATIONS
Acalabrutinib was associated with favorable PFS and OS compared with frontline CLL therapies and ranked highest in treatment efficacy over the other comparators. The NMA was limited by heterogeneity in patient baseline characteristics across trials, variable treatment regimens, and short study follow-up times. Despite these limitations, the NMA provides insights into the relative efficacy of acalabrutinib compared with frontline CLL therapies in the absence of head-to-head clinical trials.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Benzamides; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Network Meta-Analysis; Pyrazines; Randomized Controlled Trials as Topic
PubMed: 33032842
DOI: 10.1016/j.clinthera.2020.08.017