-
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 -
Multiple Sclerosis and Related Disorders Nov 2018Psychiatric comorbidity is prevalent in persons with multiple sclerosis (MS). Few studies have assessed whether second-generation disease-modifying therapies (DMT) are...
BACKGROUND
Psychiatric comorbidity is prevalent in persons with multiple sclerosis (MS). Few studies have assessed whether second-generation disease-modifying therapies (DMT) are associated with adverse psychiatric effects.
OBJECTIVE
We aimed to systematically review the literature regarding the APEs associated with natalizumab, fingolimod, dimethyl fumarate, teriflunomide and alemtuzumab in MS. As a secondary objective, we evaluated changes in anxiety or depression scores following treatment with the aforementioned DMTs.
METHODS
We searched MEDLINE, EMBASE, International Pharmaceutical Abstracts, PsychINFO, Central Register of Controlled Trials & Cochrane database of systematic reviews for published studies, and clinicaltrials.gov and regulatory documents from the US and Canada for unpublished studies. Data sources were searched from inception to September 2017. Studies reporting adverse psychiatric effects involving any DMT of interest were included. We report the incidence proportions of the adverse psychiatric effects and, where applicable, risk differences between DMT-exposed and unexposed individuals along with the corresponding 95% confidence intervals. We calculated the standardized mean differences (SMD) of changes in anxiety and depression scores if reported as study outcomes, and pooled the data using random effects meta-analysis.
RESULTS
Of 4389 abstracts screened, 78 met the inclusion criteria, including 48 clinical trials, 28 observational studies and 2 case reports. Depression was the most commonly reported adverse psychiatric effect. Incidence proportions for all adverse psychiatric effects ranged from 0 to 24.7%. None of the DMT studied were associated with a statistically significant increased risk of any adverse psychiatric effect (range of risk difference: -7.69% [95%CI: -16.06%, 5.56%] to 6.67 [-8.56, 15.59]). Eighteen studies examined changes in depression or anxiety following fingolimod, natalizumab or dimethyl fumarate treatment; depression symptoms improved in fingolimod-treated groups (SMD [95%CI]: 1.18 [0.17, 2.19]). We did not identify studies examining changes in these outcomes following treatment with any of the other DMTs.
CONCLUSION
The DMTs reviewed were not associated with an increased risk of adverse psychiatric effect in MS, and some may reduce the incidence of depressive symptoms. This may reflect either a positive direct effect (e.g. immune modulation) or an indirect effect arising due to a positive impact on disease activity or course.
Topics: Anxiety; Depression; Humans; Immunosuppressive Agents; Multiple Sclerosis
PubMed: 30248593
DOI: 10.1016/j.msard.2018.09.008 -
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 -
Transplantation Proceedings Dec 2018The Publisher regrets that this article is an accidental duplication of an article that has already been published in Transplant Proc. 2018; 50 (10):3739-3747,...
WITHDRAWN: Acute Cellular Rejection and Infection Rates in Alemtuzumab vs Traditional Induction Therapy Agents for Lung and Heart Transplantation: A Systematic Review and Meta-analysis.
The Publisher regrets that this article is an accidental duplication of an article that has already been published in Transplant Proc. 2018; 50 (10):3739-3747, https://doi.org/10.1016/j.transproceed.2018.08.018. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
PubMed: 30577265
DOI: 10.1016/j.transproceed.2018.08.018 -
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 -
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 -
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