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Oncology Nursing Forum Jan 2019Subcutaneous (SC) formulations for monoclonal antibodies (mAbs) must be evaluated for efficacy and safety in comparison with preexisting IV formulations to identify...
PROBLEM IDENTIFICATION
Subcutaneous (SC) formulations for monoclonal antibodies (mAbs) must be evaluated for efficacy and safety in comparison with preexisting IV formulations to identify potential benefits and risks.
LITERATURE SEARCH
This is a systematic review of clinical trials. MEDLINE®/PubMed, EMBASE, Cochrane Library, LILACS (Latin American and Caribbean Health Sciences Literature), and reference lists were searched for relevant studies.
DATA EVALUATION
Data regarding efficacy and safety were registered in a form designed for this review. Risk of bias was assessed using the Jadad scale.
SYNTHESIS
SC administration of alemtuzumab, trastuzumab, and rituximab presented therapeutic efficacy with similar safety profiles compared to their respective IV formulations, except for the higher prevalence of local adverse events following SC administration.
IMPLICATIONS FOR PRACTICE
SC mAbs require slow administration (no less than five minutes), and the injection site should be changed at each cycle. Patient guidelines should include information about expected adverse effects, signs or symptoms of side effects requiring emergency care, and how to reduce potential discomfort caused by the injection.
Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Female; Humans; Male; Middle Aged; Neoplasms; Rituximab; Treatment Outcome
PubMed: 30547957
DOI: 10.1188/19.ONF.E38-E47 -
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 -
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 -
Neurologia I Neurochirurgia Polska 2022This study was performed to compare probabilities of SDI on the Expanded Disability Status Scale (EDSS) in patients with relapsing-remitting multiple sclerosis (RRMS),... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
This study was performed to compare probabilities of SDI on the Expanded Disability Status Scale (EDSS) in patients with relapsing-remitting multiple sclerosis (RRMS), treated with cladribine tablets (CT) or fingolimod (FTY), natalizumab (NAT), alemtuzumab (ALE) and ocrelizumab (OCR).
CLINICAL RATIONALE FOR THE STUDY
Progression of neurological disability as measured by the EDSS has been a common endpoint in multiple sclerosis (MS) trials. Novel therapies can not only slow this process, but in some patients even reverse it. This effect can be measured by the sustained disability improvement (SDI) - an endpoint that seems to continuously gain importance in clinical practice. Despite that, SDI has rarely been explored as an outcome in MS clinical studies, mostly as post-hoc analyses from randomised trials or as retrospective analyses based on patient registry records.
MATERIAL AND METHODS
A systematic review was conducted in Medline, Embase and Cochrane to identify clinical trials (RCT or non-RCT) evaluating 6-month SDI. An indirect comparison via network meta-analysis (NMA) was performed. Bayesian inference with Markov chains Monte Carlo methods were applied.
RESULTS
Eight trials presenting SDI results and applicable for NMA were included: six non-RCTs, with control groups selected by propensity score matching, and two RCTs. NMA results revealed that probability of achieving 6-month SDI with CT was significantly higher compared to all other high efficacy disease-modifying drugs with available data - HR (95% Crl - Bayesian Credibility Interval) vs. FTY: 4.98 (2.11-11.79); vs. NAT: 3.12 (1.31-7.27); vs. ALE: 9.29 (3.40-25.21). The main results were confirmed in the sensitivity analyses.
CONCLUSIONS
Of all considered therapies, treatment with cladribine tablets was associated with a higher probability of sustained disability improvement in RRMS patients. As this conclusion is based on available clinical data of limited quality, future studies, as well as real-world data, would be valuable to provide further evidence regarding the comparative effectiveness of RRMS therapies.
Topics: Humans; Cladribine; Multiple Sclerosis; Immunosuppressive Agents; Network Meta-Analysis; Retrospective Studies; Bayes Theorem; Multiple Sclerosis, Relapsing-Remitting; Tablets
PubMed: 36421066
DOI: 10.5603/PJNNS.a2022.0068 -
Current Pharmaceutical Design 2024Co-signaling and adhesion molecules are important elements for creating immune synapses between T lymphocytes and antigen-presenting cells; they positively or negatively...
BACKGROUND
Co-signaling and adhesion molecules are important elements for creating immune synapses between T lymphocytes and antigen-presenting cells; they positively or negatively regulate the interaction between a T cell receptor with its cognate antigen, presented by the major histocompatibility complex.
OBJECTIVES
We conducted a systematic review on the effects of High Efficacy Disease Modifying Drugs (HEDMDs) for Multiple Sclerosis (MS) on the co-signaling and adhesion molecules that form the immune synapse.
METHODS
We searched EMBASE, MEDLINE, and other sources to identify clinical or preclinical reports on the effects of HEDMDs on co-signaling and adhesion molecules that participate in the formation of immune synapses in patients with MS or other autoimmune disorders. We included reports on cladribine tablets, anti- CD20 monoclonal antibodies, S1P modulators, inhibitors of Bruton's Tyrosine Kinase, and natalizumab.
RESULTS
In 56 eligible reports among 7340 total publications, limited relevant evidence was uncovered. Not all co-signaling and adhesion molecules have been studied in relation to every HEDMD, with more data being available on the anti-CD20 monoclonal antibodies (that affect CD80, CD86, GITR and TIGIT), cladribine tablets (affecting CD28, CD40, ICAM-1, LFA-1) and the S1P modulators (affecting CD86, ICAM-1 and LFA-1) and less on Natalizumab (affecting CD80, CD86, CD40, LFA-1, VLA-4) and Alemtuzumab (affecting GITR and CTLA-4).
CONCLUSION
The puzzle of HEDMD effects on the immune synapse is far from complete. The available evidence suggests that distinguishing differences exist between drugs and are worth pursuing further.
Topics: Animals; Humans; Cell Adhesion Molecules; Immunological Synapses; Multiple Sclerosis
PubMed: 38343058
DOI: 10.2174/0113816128288102240131053205 -
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 -
CNS Neuroscience & Therapeutics May 2022Previous research has shown that cerebral T1 hypointense lesions are positively correlated with the disability of multiple sclerosis (MS) patients. Hence, they could be... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Previous research has shown that cerebral T1 hypointense lesions are positively correlated with the disability of multiple sclerosis (MS) patients. Hence, they could be used as an objective marker for evaluating the progression of the disease. Up to this date, there has not been a systematic evaluation of the effects of disease-modifying therapies (DMTs) on this prognostic marker.
OBJECTIVES
To evaluate the effects of FDA-approved DMTs on the numbers and volume of T1 hypointense lesions in adult patients with MS.
METHODS
We included studies with the mentioned desired outcomes. In March 2021, we searched MEDLINE (Ovid), Embase, and CENTRAL to find relevant studies. All included studies were assessed for the risk of bias using the RoB-2 tool. Extracted data were analyzed using a random-effects model. Certainty of evidence was assessed using GRADE.
RESULTS
Thirteen studies with 7484 participants were included. Meta-analysis revealed the mean difference between the intervention and comparator groups for the number of lesions was -1.3 (95% CI: -2.1, -0.5) and for the mean volume of lesions was -363.1 (95% CI: -611.6, -114.6). Certainty of evidence was judged to be moderate. Heterogeneity was considerable.
DISCUSSION
DMTs reduce the number and volume of T1 hypointense lesions. Although, these findings must be interpreted cautiously due to the high values of heterogeneity.
Topics: Adult; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
PubMed: 35218155
DOI: 10.1111/cns.13815 -
Clinical Rheumatology Feb 2023Cutaneo us vasculitis (CV) has a broad spectrum of etiologies, and drugs are one of the main culprits. With the increasing use of targeted therapies in medicine,...
Cutaneo us vasculitis (CV) has a broad spectrum of etiologies, and drugs are one of the main culprits. With the increasing use of targeted therapies in medicine, especially in rheumatology and oncology, the number of CV cases reported due to these drugs has increased. Therefore, the recognition and treatment of CV associated with targeted agents have become more and more important. In the literature, anti-TNFs (n = 73, 59.5%), secukinumab (n = 7, 6%), rituximab (n = 5, 4%), tocilizumab (n = 1, 0.8%), ustekinumab (n = 8, 6.5%), abatacept (n = 3, 2.4%), Janus kinase inhibitors (n = 3, 2.4%), alemtuzumab (n = 3, 2.4%), and immune checkpoint inhibitors (n = 20, 16%) have been reported as responsible agents. However, our knowledge of the pathogenetic mechanisms is fairly limited, and the standardized management is yet to be established. Furthermore, though it is uncommon, this complication may pose a safety issue. In this manuscript, we reviewed the literature on CV with or without systemic involvement related to targeted agents. We also proposed the pathogenetic mechanisms of these adverse events. Thus, we aimed to make it easier for clinicians to manage similar cases by reviewing the diagnosis and treatment processes.
Topics: Humans; Abatacept; Antineoplastic Agents; Rituximab; Skin Diseases, Vascular; Ustekinumab; Vasculitis
PubMed: 36369405
DOI: 10.1007/s10067-022-06406-6 -
The Permanente Journal 2016B-cell prolymphocytic leukemia (B-PLL) is a rare, aggressive leukemia distinct from chronic lymphocytic leukemia, with median survival of only 3 years. B-PLL is... (Review)
Review
INTRODUCTION
B-cell prolymphocytic leukemia (B-PLL) is a rare, aggressive leukemia distinct from chronic lymphocytic leukemia, with median survival of only 3 years. B-PLL is resistant to most chemotherapy and newer targeted therapies such as alemtuzumab and thalidomide. Phenylethyl isothiocyanate (PEITC) is a natural compound from horseradish with evidence for therapeutic potential in multiple leukemia types.
CASE PRESENTATION
Here we present a case report of a 53-year-old man whose chronic lymphocytic leukemia transformed to end-stage B-PLL, disqualifying him for allogenic stem cell transplantation. He was treated with PEITC followed by salvage R-CHOP (Rituximab, Cyclophosphamide, Hydroxydaunorubicin [doxorubicin hydrochloride], Oncovin [vincristine sulfate], Prednisone or Prednisolone) chemotherapy, which led to normalized white blood cell count and disease stabilization that requalified him for allogenic peripheral stem-cell transplant therapy. We conducted a systematic review to analyze and interpret the potential contribution of PEITC to his unexpectedly favorable R-CHOP response. Following sequential 8 weeks of PEITC/pentostatin and 6 cycles of R-CHOP, the patient received allogenic peripheral blood stem cell transplant on an outpatient basis and remains well at the time of this publication, with no evidence of CD20+ small B-cells.
DISCUSSION
Given the limited data for R-CHOP in B-PLL, this patient's recovery suggests presensitization of B-PLL cells toward R-CHOP, potentially justifying further investigation.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Isothiocyanates; Leukemia, Prolymphocytic, B-Cell; Male; Middle Aged; Outcome Assessment, Health Care; Salvage Therapy
PubMed: 27168399
DOI: 10.7812/TPP/15-153 -
The Cochrane Database of Systematic... Apr 2017The treatment of multiple sclerosis has changed over the last 20 years. The advent of disease-modifying drugs in the mid-1990s heralded a period of rapid progress in the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The treatment of multiple sclerosis has changed over the last 20 years. The advent of disease-modifying drugs in the mid-1990s heralded a period of rapid progress in the understanding and management of multiple sclerosis. With the support of magnetic resonance imaging early diagnosis is possible, enabling treatment initiation at the time of the first clinical attack. As most of the disease-modifying drugs are associated with adverse events, patients and clinicians need to weigh the benefit and safety of the various early treatment options before taking informed decisions.
OBJECTIVES
1. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for the treatment of a first clinical attack suggestive of MS compared either with placebo or no treatment;2. to assess the relative efficacy and safety of disease-modifying drugs according to their benefit and safety;3. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for treatment started after a first attack ('early treatment') compared with treatment started after a second attack or at another later time point ('delayed treatment').
SEARCH METHODS
We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, MEDLINE, Embase, CINAHL, LILACS, clinicaltrials.gov, the WHO trials registry, and US Food and Drug Administration (FDA) reports, and searched for unpublished studies (until December 2016).
SELECTION CRITERIA
We included randomised and observational studies that evaluated one or more drugs as monotherapy in adult participants with a first clinical attack suggestive of MS. We considered evidence on alemtuzumab, azathioprine, cladribine, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, immunoglobulins, interferon beta-1b, interferon beta-1a (Rebif®, Avonex®), laquinimod, mitoxantrone, natalizumab, ocrelizumab, pegylated interferon beta-1a, rituximab and teriflunomide.
DATA COLLECTION AND ANALYSIS
Two teams of three authors each independently selected studies and extracted data. The primary outcomes were disability-worsening, relapses, occurrence of at least one serious adverse event (AE) and withdrawing from the study or discontinuing the drug because of AEs. Time to conversion to clinically definite MS (CDMS) defined by Poser diagnostic criteria, and probability to discontinue the treatment or dropout for any reason were recorded as secondary outcomes. We synthesized study data using random-effects meta-analyses and performed indirect comparisons between drugs. We calculated odds ratios (OR) and hazard ratios (HR) along with relative 95% confidence intervals (CI) for all outcomes. We estimated the absolute effects only for primary outcomes. We evaluated the credibility of the evidence using the GRADE system.
MAIN RESULTS
We included 10 randomised trials, eight open-label extension studies (OLEs) and four cohort studies published between 2010 and 2016. The overall risk of bias was high and the reporting of AEs was scarce. The quality of the evidence associated with the results ranges from low to very low. Early treatment versus placebo during the first 24 months' follow-upThere was a small, non-significant advantage of early treatment compared with placebo in disability-worsening (6.4% fewer (13.9 fewer to 3 more) participants with disability-worsening with interferon beta-1a (Rebif®) or teriflunomide) and in relapses (10% fewer (20.3 fewer to 2.8 more) participants with relapses with teriflunomide). Early treatment was associated with 1.6% fewer participants with at least one serious AE (3 fewer to 0.2 more). Participants on early treatment were on average 4.6% times (0.3 fewer to 15.4 more) more likely to withdraw from the study due to AEs. This result was mostly driven by studies on interferon beta 1-b, glatiramer acetate and cladribine that were associated with significantly more withdrawals for AEs. Early treatment decreased the hazard of conversion to CDMS (HR 0.53, 95% CI 0.47 to 0.60). Comparing active interventions during the first 24 months' follow-upIndirect comparison of interferon beta-1a (Rebif®) with teriflunomide did not show any difference on reducing disability-worsening (OR 0.84, 95% CI 0.43 to 1.66). We found no differences between the included drugs with respect to the hazard of conversion to CDMS. Interferon beta-1a (Rebif®) and teriflunomide were associated with fewer dropouts because of AEs compared with interferon beta-1b, cladribine and glatiramer acetate (ORs range between 0.03 and 0.29, with substantial uncertainty). Early versus delayed treatmentWe did not find evidence of differences between early and delayed treatments for disability-worsening at a maximum of five years' follow-up (3% fewer participants with early treatment (15 fewer to 11.1 more)). There was important variability across interventions; early treatment with interferon beta-1b considerably reduced the odds of participants with disability-worsening during three and five years' follow-up (OR 0.52, 95% CI 0.32 to 0.84 and OR 0.57, 95% CI 0.36 to 0.89). The early treatment group had 19.6% fewer participants with relapses (26.7 fewer to 12.7 fewer) compared to late treatment at a maximum of five years' follow-up and early treatment decreased the hazard of conversion to CDMS at any follow-up up to 10 years (i.e. over five years' follow-up HR 0.62, 95% CI 0.53 to 0.73). We did not draw any conclusions on long-term serious AEs or discontinuation due to AEs because of inadequacies in the available data both in the included OLEs and cohort studies.
AUTHORS' CONCLUSIONS
Very low-quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses. The advantage of early treatment compared with delayed on disability-worsening was heterogeneous depending on the actual drug used and based on very low-quality evidence. Low-quality evidence suggests that the chances of relapse are less with early treatment compared with delayed. Early treatment reduced the hazard of conversion to CDMS compared either with placebo, no treatment or delayed treatment, both in short- and long-term follow-up. Low-quality evidence suggests that early treatment is associated with fewer participants with at least one serious AE compared with placebo. Very low-quality evidence suggests that, compared with placebo, early treatment leads to more withdrawals or treatment discontinuation due to AEs. Difference between drugs on short-term benefit and safety was uncertain because few studies and only indirect comparisons were available. Long-term safety of early treatment is uncertain because of inadequately reported or unavailable data.
Topics: Adjuvants, Immunologic; Cladribine; Cohort Studies; Crotonates; Disease Progression; Glatiramer Acetate; Humans; Hydroxybutyrates; Immunosuppressive Agents; Interferon beta-1a; Multiple Sclerosis; Nitriles; Publication Bias; Randomized Controlled Trials as Topic; Recurrence; Time Factors; Toluidines
PubMed: 28440858
DOI: 10.1002/14651858.CD012200.pub2