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Autoimmunity Reviews Jun 2017Immunotherapy initiated early after first presentation of relapsing-remitting multiple sclerosis is associated with improved long-term outcomes. One can therefore... (Review)
Review
BACKGROUND
Immunotherapy initiated early after first presentation of relapsing-remitting multiple sclerosis is associated with improved long-term outcomes. One can therefore speculate that early initiation of highly effective immunotherapies, with an average efficacy that is superior to the typical first-line therapies, could further improve relapse and disability outcomes. However, the most common treatment strategy is to commence first-line therapies, followed by treatment escalation in patients who continue to experience on-treatment disease activity. While this monitoring approach is logical, the current lack of effective regenerative or remyelinating therapies behoves us to consider high-efficacy treatment strategies from disease onset (including induction therapy) in order to prevent irreversible disability.
OBJECTIVE
In this systematic review, we evaluate the effect of high-efficacy immunotherapies at different stages of MS.
METHODS
A systematic review of literature reporting outcomes of treatment with fingolimod, natalizumab or alemtuzumab at different stages of MS was carried out.
RESULTS AND CONCLUSIONS
Twelve publications reporting relevant information were included in the systematic review. The literature suggests that treatment with high-efficacy immunotherapies is more potent in suppressing relapse activity when initiated early vs. with a delay after the MS diagnosis. The evidence reported for disability and MRI outcomes is inconclusive.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Treatment Outcome
PubMed: 28428119
DOI: 10.1016/j.autrev.2017.04.010 -
BioDrugs : Clinical Immunotherapeutics,... Aug 2015Monoclonal antibody (mAb)-based orphan drugs have led to advances in the treatment of diseases by selectively targeting molecule functions. However, their high treatment... (Review)
Review
BACKGROUND
Monoclonal antibody (mAb)-based orphan drugs have led to advances in the treatment of diseases by selectively targeting molecule functions. However, their high treatment costs impose a substantial cost burden on patients and society.
OBJECTIVES
The study aimed to systematically review cost-effectiveness evidence of mAb orphan drugs.
METHODS
Ovid MEDLINE(®), EMBASE(®), and PsycINFO(®) were searched in June 2014 and articles were selected if they conducted economic evaluations of the mAb orphan drugs that had received marketing approval in the USA. The quality of the selected studies was assessed using the Quality of Health Economic Studies (QHES) instrument.
RESULTS
We reviewed 16 articles that included 24 economic evaluations of nine mAb orphan drugs. Six of these nine drugs were included in cost-utility analysis studies, whereas three drugs were included in cost-effectiveness analysis studies. Previous cost-utility analysis studies revealed that four mAb orphan drugs (cetuximab, ipilimumab, rituximab, and trastuzumab) were found to be cost effective; one drug (bevacizumab) was not cost effective; and one drug (infliximab) was not consistent across the studies. Prior cost-effectiveness analysis studies which included three mAb orphan drugs (adalimumab, alemtuzumab, and basiliximab) showed that the incremental cost per effectiveness gained for these drugs ranged from $US4669 to $Can52,536 Canadian dollars. The quality of the included studies was good or fair with the exception of one study.
CONCLUSIONS
Some mAb orphan drugs were reported as cost effective under the current decision-making processes. Use of these expensive drugs, however, can raise an equity issue which concerns fairness in access to treatment. The issue of equal access to drugs needs to be considered alongside other societal values in making the final health policy decisions.
Topics: Antibodies, Monoclonal; Cost-Benefit Analysis; Decision Making; Drug Approval; Humans; Orphan Drug Production; Rare Diseases
PubMed: 26263903
DOI: 10.1007/s40259-015-0135-4 -
The Journal of Heart and Lung... Sep 2017Long-term success of lung transplantation is limited by the development of chronic lung allograft dysfunction (CLAD), of which bronchiolitis obliterans syndrome (BOS) is... (Comparative Study)
Comparative Study Review
BACKGROUND
Long-term success of lung transplantation is limited by the development of chronic lung allograft dysfunction (CLAD), of which bronchiolitis obliterans syndrome (BOS) is the most common form. This systematic review sought to identify the current evidence base for CLAD-BOS therapies after initial immunosuppressive treatment strategies.
METHODS
The MEDLINE, Embase, and Cochrane Library databases from inception to May 3, 2016, were searched using keywords relating to CLAD-BOS, study designs, and treatments of interest, including extracorporeal photopheresis (ECP), aerosolized cyclosporine, total lymphoid irradiation (TLI), alemtuzumab, and montelukast. Titles, abstracts, and full texts were screened by 2 independent reviewers to identify studies of CLAD-BOS second-line therapy in adult lung transplant patients. Quality was assessed according to the Downs and Black checklist.
RESULTS
Of the 936 individual citations identified, 47 reports of 40 studies met inclusion criteria, including 17 full publications, 11 recent (2015-2016), and 12 older (pre-2015) congress proceedings. Most of the full publications and recent abstracts investigated ECP (n = 11), TLI (n = 5), alemtuzumab (n = 4), and montelukast (n = 2). Most studies were uncontrolled and retrospective. Compared with standard therapy alone, improved lung function and survival was reported for ECP in 2 studies without randomization, with lower-quality evidence for improved lung function for TLI, montelukast, and aerosolized cyclosporine.
CONCLUSIONS
Because most identified studies were of retrospective and uncontrolled design, comparison of treatment effects was limited. Available evidence suggests stabilized lung function after ECP in combination with established immunosuppressive regimens in late-line CLAD-BOS treatment, with fewer data for TLI, montelukast, and aerosolized cyclosporine.
Topics: Allografts; Bronchiolitis Obliterans; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Lung Transplantation; Lymphatic Irradiation; Male; Photopheresis; Primary Graft Dysfunction; Prognosis; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Syndrome; Transplantation Immunology; Treatment Outcome
PubMed: 28662986
DOI: 10.1016/j.healun.2017.05.030 -
Seminars in Arthritis and Rheumatism Oct 2015To examine, separately, in children and adults with autoimmune chronic uveitis (ACU), the evidence regarding the effectiveness and the safety of switching to a... (Review)
Review
OBJECTIVE
To examine, separately, in children and adults with autoimmune chronic uveitis (ACU), the evidence regarding the effectiveness and the safety of switching to a non-anti-TNF biologic modifier immunosuppressant treatment (NTT) currently available in clinical practice.
METHODS
A systematic search between January 2000 and April 2014 was conducted using EMBASE, Ovid MEDLINE, Evidence Based Medicine Reviews-ACP Journal Club, Cochrane libraries, and EBM Reviews. Studies investigating the efficacy of NTT as a biologic modifier immunosuppressant medication for ACU, refractory to topical and/or systemic steroid therapy, were eligible for inclusion. The primary outcome measure was the improvement of intraocular inflammation, as defined by the SUN working group criteria. We determined a combined estimate of the proportion of subjects responding to NTT.
RESULTS
We initially identified 526 articles, of which 89 were potentially eligible. From the selection process, a total of 10 retrospective chart reviews and a randomized single-blind controlled study, providing a total of 12 children and 34 adults, were deemed eligible: 3 articles looked at rituximab, 3 at abatacept, 3 at tocilizumab, and the remaining 1 at alemtuzumab and the other at anakinra. Before the NTT treatment, all the eligible subjects received several combinations of one or more DMARDs and at least one anti-TNF strategy. With the exclusion of 7 adults enrolled in the RCT, 8 of 12 children and 18 of 27 adults responded to NTT treatment: 0.66 was the combined estimate of the proportion of subjects improving on NTT treatment in children (95% CI: 0.46-0.99) and in adults (95% CI: 0.49-0.84). Further statistical comparison between different NTT strategies was not possible due to the small sample size.
CONCLUSION
Although randomized controlled trials are needed, the available evidence suggests the clinical use of a NTT strategy in selected categories of ACU, refractory to previous course of immunosuppressive treatment, DMARDs, as well as anti-TNFα, in adults as well as children.
Topics: Abatacept; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Biological Products; Humans; Interleukin 1 Receptor Antagonist Protein; Rituximab; Treatment Outcome; Uveitis
PubMed: 26164255
DOI: 10.1016/j.semarthrit.2015.05.006 -
Transplantation Proceedings Dec 2018Heart and lung transplantation is a high-risk procedure requiring intensive immunosuppressive therapy for preventing organ rejection. Alemtuzumab, a CD52-specific... (Meta-Analysis)
Meta-Analysis
Acute Cellular Rejection and Infection Rates in Alemtuzumab vs Traditional Induction Therapy Agents for Lung and Heart Transplantation: A Systematic Review and Meta-analysis.
BACKGROUND AND OBJECTIVES
Heart and lung transplantation is a high-risk procedure requiring intensive immunosuppressive therapy for preventing organ rejection. Alemtuzumab, a CD52-specific monoclonal antibody, is increasingly used for induction therapy compared with conventional agents. However, there has been no systematic review comparing its efficacy with traditional therapeutic drugs.
METHODS
PubMed and EMBASE were searched to October 1, 2017, for articles on alemtuzumab in cardiothoracic transplant surgery. Of the 433 studies retrieved, 8 were included in the final meta-analysis.
RESULTS
In lung transplantation, alemtuzumab use was associated with lower odds of acute cellular rejection compared with antithymocyte globulin (odds ratio [OR], 0.21; 95% CI, 0.11-0.40; P < .001), lower acute rejection rates (OR, 0.12; 95% CI, 0.03-0.55; P < .01), and infection rates (OR, 0.69; 95% CI, 0.35-1.36; P = .33) when compared with basiliximab. Multivariate meta-regression analysis found that mean age, male sex, single lung transplant, double lung transplant, cytomegalovirus or Epstein-Barr virus status, idiopathic pulmonary fibrosis, cystic fibrosis, and mean ischemic time did not significantly influence acute rejection outcomes. For heart transplantation, alemtuzumab use was associated with lower acute rejection rates when compared with tacrolimus (OR, 0.44; 95% CI, 0.30-0.66; P < .001).
CONCLUSIONS
Alemtuzumab use was associated with lower rejection rates when compared with conventional induction therapy agents (antithymocyte globulin, basiliximab, and tacrolimus) in heart and lung transplantation. However, this was based on observational studies. Randomized controlled trials are needed to verify its clinical use.
Topics: Adult; Alemtuzumab; Antibodies, Monoclonal, Humanized; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Lung Transplantation; Male; Middle Aged
PubMed: 30577263
DOI: 10.1016/j.transproceed.2018.08.044 -
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 -
Current Medical Research and Opinion Aug 2018To assess the comparative efficacy and safety of cladribine tablets versus alternative disease modifying treatments (DMTs) in patients with active relapsing-remitting... (Comparative Study)
Comparative Study
OBJECTIVE
To assess the comparative efficacy and safety of cladribine tablets versus alternative disease modifying treatments (DMTs) in patients with active relapsing-remitting multiple sclerosis (RRMS), and in a subgroup with high disease activity (HRA + DAT), using systematic literature review (SLR) and network meta-analysis (NMA).
METHODS
MEDLINE, Embase, MEDLINE In-Process and CENTRAL databases were systematically searched to identify English-language publications of relevant studies of approved DMTs for RRMS. Searches were conducted from database inception to January 2017. Conference websites and trial registries were also searched. NMA considered the effects of DMTs on annualized relapse rate (ARR), confirmed disease progression (CDP), no evidence of disease activity (NEDA) and safety.
RESULTS
Of 10,825 articles retrieved and screened, 44 studies assessing 12 DMTs contributed to the NMA. In patients with active RRMS, cladribine tablets were associated with a significant 58% reduction in ARR versus placebo (p < .05); cladribine tablets were similar or significantly better than other DMT regimens and ranked fourth among DMTs, behind alemtuzumab, natalizumab and ocrelizumab. For CDP for 6 months and NEDA, improvements with cladribine tablets were significantly greater than those of placebo (p < .05), with no comparator DMT demonstrating significantly better results. Similar findings were reported in the HRA + DAT population. Overall adverse event risk for cladribine tablets did not differ significantly from that of placebo and most alternative DMTs.
CONCLUSION
In this first NMA to consider cladribine tablets, ocrelizumab and daclizumab for treatment of RRMS, cladribine tablets are a comparatively effective and safe alternative to other DMTs in both active RRMS and HRA + DAT populations.
Topics: Alemtuzumab; Cladribine; Humans; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Network Meta-Analysis; Tablets
PubMed: 29149804
DOI: 10.1080/03007995.2017.1407303 -
Leukemia & Lymphoma Sep 2016Randomized clinical trials that compared chlorambucil to different regimens, for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) do not... (Meta-Analysis)
Meta-Analysis Review
Randomized clinical trials that compared chlorambucil to different regimens, for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) do not support an overall survival (OS) benefit. To assess the efficacy and safety of chlorambucil as frontline treatment, we conducted a systematic review and meta-analysis of randomized controlled trials. OS was the primary outcome. Meta-analysis of 18 trials that compared purine analogs, alkylators, alemtuzumab and ibrutinib to chlorambucil demonstrated no OS benefit for therapy without chlorambucil over chlorambucil (pooled HR 0.99, 95% CI 0.91-1.08; 4133 patients). PFS was longer with purine analogs compared with chlorambucil with an increased risk of infection. The risk of secondary malignancies was not increased with chlorambucil. In conclusion, our study showed that chlorambucil is an acceptable chemotherapy backbone for unfit patients with CLL. Purine analogs should be preferred in fit younger patients because of longer PFS. Future trials should focus on unfit patients who are underrepresented in clinical trials.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Disease Progression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms, Second Primary; Prognosis; Proportional Hazards Models; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 26980554
DOI: 10.3109/10428194.2016.1154956 -
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 -
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