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The Lancet. Gastroenterology &... Feb 2022Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission... (Randomized Controlled Trial)
Randomized Controlled Trial
Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial.
BACKGROUND
Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents.
METHODS
HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18-80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov, NCT02100696.
FINDINGS
HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114).
INTERPRETATION
HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14.
FUNDING
F Hoffmann-La Roche.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Asia; Colitis, Ulcerative; Europe; Female; Gastrointestinal Agents; Humans; Injections, Subcutaneous; Male; Middle Aged; Middle East; North America; Oceania; Remission Induction; Severity of Illness Index; South America; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Young Adult
PubMed: 34798039
DOI: 10.1016/S2468-1253(21)00298-3 -
Transplantation and Cellular Therapy May 2021Mantle cell lymphoma (MCL) is a subtype of B cell non-Hodgkin lymphoma characterized by a heterogeneous clinical presentation. Patients who demonstrate an objective... (Review)
Review
Mantle cell lymphoma (MCL) is a subtype of B cell non-Hodgkin lymphoma characterized by a heterogeneous clinical presentation. Patients who demonstrate an objective response to induction therapy(ies) and are eligible for intensive therapies are offered an autologous hematopoietic cell transplant (HCT) as front-line consolidation followed by rituximab maintenance. Allogeneic HCT is an option for younger and fit patients with high-risk disease or in patients who have relapsed after autologous HCT. Recent advances in T cell engineering brought chimeric antigen receptor T cell (CAR T) therapy from the bench to the bedside, with brexucabtagene autoleucel being the first CAR T product approved by the US Food and Drug Administration for use in relapsed/refractory MCL. In this comprehensive review, we summarize the literature on available cellular therapies for MCL and present a treatment algorithm that incorporates HCT, autologous or allogeneic, and CAR T therapies.
Topics: Adult; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Transplantation, Autologous; United States
PubMed: 33965173
DOI: 10.1016/j.jtct.2021.01.026 -
Clinical Medicine (London, England) Nov 2023Crohn's disease (CD) is a chronic, relapsing and remitting inflammatory bowel disease (IBD) that is increasing in incidence and prevalence globally. Management aims to...
Crohn's disease (CD) is a chronic, relapsing and remitting inflammatory bowel disease (IBD) that is increasing in incidence and prevalence globally. Management aims to achieve endoscopic healing, symptom resolution and improvement in quality of life. Therapeutic approaches in CD vary depending on disease phenotype. Thiopurines are important in steroid-sparing maintenance therapy, while anti-tumour necrosis factor agents play a fundamental role, especially in fistulising CD. Suboptimal response to these medications may require escalation to other immunosuppressive and biologic therapies, and surgical intervention is still required in a proportion of patients. Tailoring treatment to target specific patient phenotypes, disease severity and patient wishes is becoming more feasible with the growing array of therapeutic options in CD.
Topics: Humans; Crohn Disease; Quality of Life; Immunosuppressive Agents; Remission Induction
PubMed: 38065612
DOI: 10.7861/clinmed.2023-0493 -
Clinical Genitourinary Cancer Aug 2015Perioperative chemotherapy provided to increase the chance of cure for localized disease and maintenance therapy for metastatic disease represent 2 distinct aspects of... (Review)
Review
Perioperative chemotherapy provided to increase the chance of cure for localized disease and maintenance therapy for metastatic disease represent 2 distinct aspects of the urothelial cancer disease treatment spectrum. The ability to access both pre- and postchemotherapy tissue in the neoadjuvant setting provides important opportunities for translational research to test novel therapies and identify predictors of response to therapy. The maintenance setting may be more complex, and study design and endpoints need to be determined on the basis of the candidate drugs' mechanisms of action and toxicity.
Topics: Antineoplastic Agents; Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Clinical Trials as Topic; Drug Discovery; Humans; Maintenance Chemotherapy; Molecular Targeted Therapy; Perioperative Period; Urinary Bladder Neoplasms
PubMed: 25987535
DOI: 10.1016/j.clgc.2015.03.003 -
Biomedical Journal Jun 2022Allograft rejection is one of the obstacles in achieving a successful vascularized composite allotransplantation (VCA). Treatments of graft rejection with lifelong... (Review)
Review
Allograft rejection is one of the obstacles in achieving a successful vascularized composite allotransplantation (VCA). Treatments of graft rejection with lifelong immunosuppression (IS) subject the recipients to a lifelong risk of cancer development and opportunistic infections. Cell therapy has recently emerged as a promising strategy to modulate the immune system, minimize immunosuppressant drug dosages, and induce allograft tolerance. In this review, the recent works regarding the use of cell therapy to improve allograft outcomes are discussed. The current data supports the safety of cell therapy. The suitable type of cell therapy in allotransplantation is clinically dependent. Bone marrow cell therapy is more suitable for the induction phase, while other cell therapies are more feasible in either the induction or maintenance phase, or for salvage of allograft rejection. Immune cell therapy focuses on modulating the immune response, whereas stem cells may have an additional role in promoting structural regenerations, such as nerve regeneration. Source, frequency, dosage, and route of cell therapy delivery are also dependent on the specific need in the clinical setting.
Topics: Cell- and Tissue-Based Therapy; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Vascularized Composite Allotransplantation
PubMed: 35042019
DOI: 10.1016/j.bj.2022.01.005 -
Current Oncology Reports Jun 2021Advanced epithelial ovarian cancer remains the most lethal gynaecological cancer. Most patients with advanced disease will relapse within 3 years after primary treatment... (Review)
Review
PURPOSE OF REVIEW
Advanced epithelial ovarian cancer remains the most lethal gynaecological cancer. Most patients with advanced disease will relapse within 3 years after primary treatment with surgery and chemotherapy. Recurrences become increasing difficult to treat due to the emergence of drug resistance and 5-year survival has changed little over the last decade. Maintenance treatment, here defined as treatment given beyond primary chemotherapy, can both consolidate the response and prolong the control of disease which is an approach to improve survival.
RECENT FINDINGS
Here we review maintenance strategies such as targeting angiogenesis, interference of DNA repair through inhibition of PARP, combinations of targeting agents, and immunotherapy and hormonal therapy. Much has been learnt from the success and challenges of these treatments that have in the last few years which led to significant reduction in disease recurrence, changed the guidelines for treatment, and established a new paradigm for the treatment of ovarian cancer.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Female; Humans; Neoplasm Recurrence, Local; Ovarian Neoplasms; Salvage Therapy
PubMed: 34125335
DOI: 10.1007/s11912-021-01088-w -
The American Journal of Gastroenterology May 2024Ulcerative colitis (UC) is a chronic condition that may require long-term treatment. We report the final efficacy and safety results of the UNIFI long-term extension... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Ulcerative colitis (UC) is a chronic condition that may require long-term treatment. We report the final efficacy and safety results of the UNIFI long-term extension study of ustekinumab in patients with UC through 4 years.
METHODS
Ustekinumab induction responders who completed 44 weeks of maintenance treatment and agreed to enter the long-term extension continued their subcutaneous maintenance therapy (90 mg ustekinumab every 8 or 12 weeks [q8w or q12w] or placebo). Starting at week 56, randomized patients could receive dose adjustment to 90 mg q8w. Symptoms and adverse events were assessed through the study; endoscopic assessment was conducted at week 200.
RESULTS
Of the 348 patients randomized to subcutaneous ustekinumab at maintenance baseline (q8w and q12w combined), 55.2% were in symptomatic remission at week 200. A greater proportion of biologic-naive patients (67.2% [117/174]) were in symptomatic remission than those with a history of biologic failure (41.6% [67/161]). Among patients in symptomatic remission at week 200, 96.4% were corticosteroid-free. Of the 171 patients with endoscopic evaluation at week 200, 81.6% (71/87) in the q12w group and 79.8% (67/84) in the q8w group had endoscopic improvement. From weeks 156 to the final safety visit (up to week 220), no deaths, major adverse cardiovascular events, or tuberculosis occurred in patients receiving ustekinumab. Nasopharyngitis, UC worsening, and upper respiratory tract infections were the most frequently reported adverse events.
DISCUSSION
The long-term efficacy of ustekinumab maintenance in patients with UC was confirmed through 4 years. No new safety signals were observed. ClinicalTrials.gov number NCT02407236.
Topics: Ustekinumab; Humans; Colitis, Ulcerative; Male; Female; Adult; Middle Aged; Maintenance Chemotherapy; Treatment Outcome; Double-Blind Method; Remission Induction; Injections, Subcutaneous
PubMed: 38095692
DOI: 10.14309/ajg.0000000000002621 -
Annals of Nutrition & Metabolism 2016Oral immunotherapy (OIT) is a promising investigational therapy for food allergy. Clinical trials in peanut, milk, egg, and wheat allergy provide evidence that OIT can... (Review)
Review
Oral immunotherapy (OIT) is a promising investigational therapy for food allergy. Clinical trials in peanut, milk, egg, and wheat allergy provide evidence that OIT can effectively desensitize a majority of individuals to a food allergen. While a portion of subjects demonstrate sustained unresponsiveness, the majority regain sensitivity with allergen avoidance. The safety and tolerability of OIT continue to limit its use in some patients. Virtually all studies report adverse reactions that are more frequent during dose escalation but may also occur during maintenance therapy. Recent studies have identified adjunctive therapies (such as omalizumab) which may mitigate adverse effects. There is a paucity of data on the long-term safety and efficacy of OIT. Further study is required before OIT is ready for routine clinical practice. This review is intended to provide the reader with an up-to-date understanding of OIT, including its mechanisms, efficacy, safety profile, and potential utility in clinical practice.
Topics: Administration, Oral; Adult; Animals; Antigens; Child; Desensitization, Immunologic; Dietary Proteins; Evidence-Based Medicine; Food Hypersensitivity; Humans; Immune Tolerance; Immunotherapy; Precision Medicine; Quality of Life; Secondary Prevention
PubMed: 27355816
DOI: 10.1159/000445391 -
International Journal of Molecular... Jun 2021Mitochondrial DNA depletion and multiple deletions syndromes (MDDS) constitute a group of mitochondrial diseases defined by dysfunctional mitochondrial DNA (mtDNA)... (Review)
Review
Mitochondrial DNA depletion and multiple deletions syndromes (MDDS) constitute a group of mitochondrial diseases defined by dysfunctional mitochondrial DNA (mtDNA) replication and maintenance. As is the case for many other mitochondrial diseases, the options for the treatment of these disorders are rather limited today. Some aggressive treatments such as liver transplantation or allogeneic stem cell transplantation are among the few available options for patients with some forms of MDDS. However, in recent years, significant advances in our knowledge of the biochemical pathomechanisms accounting for dysfunctional mtDNA replication have been achieved, which has opened new prospects for the treatment of these often fatal diseases. Current strategies under investigation to treat MDDS range from small molecule substrate enhancement approaches to more complex treatments, such as lentiviral or adenoassociated vector-mediated gene therapy. Some of these experimental therapies have already reached the clinical phase with very promising results, however, they are hampered by the fact that these are all rare disorders and so the patient recruitment potential for clinical trials is very limited.
Topics: Animals; Combined Modality Therapy; DNA Replication; DNA, Mitochondrial; Disease Management; Disease Susceptibility; Gene Expression Regulation; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Mutation
PubMed: 34208592
DOI: 10.3390/ijms22126447 -
Journal of Ovarian Research Nov 2019Epithelial ovarian cancer (EOC) is usually diagnosed late at an advanced stage. Though EOC initially responds to treatment, the recurrence rate is pretty high. The... (Review)
Review
Epithelial ovarian cancer (EOC) is usually diagnosed late at an advanced stage. Though EOC initially responds to treatment, the recurrence rate is pretty high. The efficacy of different targeted therapies reduces with each recurrence. Hence there is need of effective maintenance therapy in recurrent EOC. Recently, polyADP-ribose polymerase (PARP) inhibitors (PARPi) have been approved both for initial treatment of EOC and as its maintenance treatment. PARPi have also been found to act regardless of BRCA status or homologous recombination (HR) deficiency. Several trials testing PARPi early in maintenance therapy are in progress and their results will shed light on the optimal timing of maintenance therapy that gives the most benefit with least toxicity. Right patient selection for maintenance treatment is also a challenge. Hence, though PARPi are emerging as a promising maintenance treatment in recurrent EOC with prolongation of progression free survival (PFS), results from further trials and overall survival (OS) data from current trials are awaited to fulfill the gaps in understanding the role of this pathway in treatment of EOC. This review discusses the current therapies for EOC, challenges in the treatment of recurrent EOC, recent developments and trials in recurrent EOC maintenance with special focus on PARPi and future perspectives.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Female; Humans; Maintenance Chemotherapy; Molecular Targeted Therapy; Mutation; Ovarian Neoplasms; Recurrence; Retreatment; Treatment Outcome
PubMed: 31685032
DOI: 10.1186/s13048-019-0579-0