Tabelecleucel for allogeneic haematopoietic stem-cell or solid organ transplant recipients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE): a phase 3, multicentre, open-label trial.

BACKGROUND: Survival in Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disease following haematopoietic stem-cell transplant (HSCT) or solid organ transplant (SOT) is poor after failure of initial therapy, indicating an urgent need for therapies for this ultra-rare disease. With recent EU marketing authorisation, tabelecleucel is the first off-the-shelf, allogeneic, EBV-specific T-cell immunotherapy to receive approval for treatment of relapsed or refractory EBV-positive post-transplant lymphoproliferative disease. We aimed to determine the clinical benefit of tabelecleucel in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease following HSCT or SOT. METHODS: In this global, multicentre, open-label, phase 3 trial, eligible patients (of any age) had biopsy-proven EBV-positive post-transplant lymphoproliferative disease, disease that was relapsed or refractory to rituximab after HSCT and rituximab with or without chemotherapy after SOT, and partially HLA-matched and appropriately HLA-restricted tabelecleucel available. Patients received tabelecleucel administered intravenously at 2 × 106 cells per kg on days 1, 8, and 15 in 35-day cycles and are assessed for up to 5 years for survival post-treatment initiation. The primary endpoint was objective response rate. All patients who received at least one dose of tabelecleucel were included in safety and efficacy analyses. This trial is registered with ClinicalTrials.gov, NCT03394365, and is ongoing. FINDINGS: From June 27, 2018, to Nov 5, 2021, 63 patients were enrolled, of whom 43 (24 [56%] male and 19 [44%] female) were included, 14 had prior HSCT, 29 had SOT. Seven (50%, 95% CI 23-77) of 14 participants in the HSCT group and 15 (52%, 33-71) of 29 participants in the SOT group had an objective response, with a median follow-up of 14·1 months (IQR 5·7-23·9) and 6·0 months (1·8-18·4), respectively. The most common grade 3 or 4 treatment-emergent adverse events were disease progression (in four [29%] of 14 in HSCT and eight [28%] of 29 in SOT) and decreased neutrophil count (in four [29%] of 14 in HSCT and four [14%] of 29 in SOT). Treatment-emergent serious adverse events were reported in 23 (53%) of 43 patients and fatal treatment-emergent adverse events in five (12%); no fatal treatment-emergent adverse event was treatment-related. There were no reports of tumour flare reaction, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, transmission of infectious diseases, marrow rejection, or infusion reactions. No events of graft-versus-host disease or SOT rejection were reported as related to tabelecleucel. INTERPRETATION: Tabelecleucel provides clinical benefit in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease, for whom there are no other approved therapies, without evidence of safety concerns seen with other adoptive T-cell therapies. These data represent a potentially transformative and accessible treatment advance for patients with relapsed or refractory disease with few treatment options. FUNDING: Atara Biotherapeutics.

Long-Term Efficacy and Safety of OnabotulinumtoxinA in Patients with Neurogenic Detrusor Overactivity Who Completed 4 Years of Treatment.

PURPOSE: We assessed the year-to-year consistency of outcomes in patients with urinary incontinence due to neurogenic detrusor overactivity who completed 4 years of onabotulinumtoxinA treatment. MATERIALS AND METHODS: Eligible patients who completed a 52-week phase 3 trial of onabotulinumtoxinA for urinary incontinence could enter a 3-year open label extension study of onabotulinumtoxinA 200 or 300 U administered as needed for symptom control. This analysis focused on 227 patients who completed the 4-year study. Outcomes assessed by year of treatment included mean treatments per year, mean change from baseline at week 6 in urinary incontinence episodes per day and the I-QOL (Incontinence Quality of Life) total summary score, the proportion of patients with 50% or greater and 100% reductions in urinary incontinence episodes per day, duration of effect and adverse events. RESULTS: Patients reported 4.3 urinary incontinence episodes per day at baseline and received 1.4 to 1.5 onabotulinumtoxinA treatments per year. The decrease in urinary incontinence following onabotulinumtoxinA consistently ranged from -3.4 to -3.9 episodes per day across 4 years. A high proportion of patients achieved 50% or greater and 100% urinary incontinence reductions in each year (range 86.6% to 94.1% and 43.6% to 57.4%, respectively). Consistent and clinically relevant improvements in I-QOL scores were observed in each treatment year. The overall median duration of effect of onabotulinumtoxinA was 9.0 months or greater (range 3.0 to 49.2) and 26.0% or more of patients experienced a duration of effect of 12 months or greater. The most common adverse event was urinary tract infection with no increased incidence with time. CONCLUSIONS: Patients with neurogenic detrusor overactivity who completed 4 years of onabotulinumtoxinA treatment experienced a consistent duration of treatment effect and year-to-year improvements in urinary incontinence and quality of life with no new safety signals.

Impact of onabotulinumtoxinA on quality of life and practical aspects of daily living: A pooled analysis of two randomized controlled trials.

OBJECTIVE: To evaluate the impact of onabotulinumtoxinA on individual domains of the quality of life questionnaires in a pooled analysis of two phase 3 trials in overactive bladder patients with urinary incontinence who were inadequately managed by ≥1 anticholinergic. METHODS: Patients received intradetrusor injections of onabotulinumtoxinA 100U (n = 557) or placebo (n = 548). The proportions of patients with a positive response (condition "greatly improved" or "improved") on the Treatment Benefit Scale, and changes in Incontinence Quality of Life scores and King's Health Questionnaire domain scores were analyzed in the overall population and subgroups with clean intermittent catheterization use and urinary tract infection status during the first 12 weeks of treatment. Responses to individual King's Health Questionnaire items were also assessed. RESULTS: Significantly greater proportions of onabotulinumtoxinA-treated patients achieved positive Treatment Benefit Scale response versus placebo (61.8% vs. 28.0%; P < 0.001). OnabotulinumtoxinA showed significantly greater improvements versus placebo in Incontinence Quality of Life total (22.5 vs. 6.6), Incontinence Quality of Life subscale scores and all domains of the King's Health Questionnaire. Notably, a similar trend was observed regardless of clean intermittent catheterization/urinary tract infection status. Additionally, onabotulinumtoxinA resulted in significantly greater improvements than the placebo in practical aspects of patients daily lives, including pad use, need to change undergarments, sleep, relationship with partner and work life/daily activities. CONCLUSION: In overactive bladder patients with urinary incontinence, onabotulinu-mtoxinA 100U demonstrated significant improvements across the individual domains of the quality of life questionnaires, regardless of clean intermittent catheterization or urinary tract infection status, and provided a positive impact on practical aspects of patients' daily lives.

Epstein-Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies.

New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community. B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS. The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein-Barr virus (EBV) and disease onset. Efforts to develop antiviral strategies for treating MS are underway. Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention.

Limitations of anticholinergic cycling in patients with overactive bladder (OAB) with urinary incontinence (UI): results from the CONsequences of Treatment Refractory Overactive bLadder (CONTROL) study.

PURPOSE: To describe treatment patterns and outcomes in wet-overactive bladder (OAB) patients treated with anticholinergics. METHODS: This study was a retrospective claims analysis linked to a one-time patient survey of members of a regional medical group located in California. Participants met the following criteria: received anticholinergic therapy between January 2008 and May 2012, based on pharmacy claims; had a diagnosis of OAB; and reported having ≥1 urinary incontinence (UI) episode per day at the time of the survey. Outcomes included the number of anticholinergics cycled through from treatment initiation until the end of follow-up (May 31, 2013); frequency of UI episodes; and patient requests for additional help for their OAB symptoms. RESULTS: A total of 620 patients were enrolled into the study. During the follow-up period, patients cycled through 1 to 6 unique anticholinergics; 65 % of the study population used only 1 anticholinergic, while 35 % used ≥2 anticholinergics. Patients reported experiencing an average of 3.5 UI episodes per day (3.6, 3.3, and 3.4 episodes for 1, 2, and ≥3 anticholinergics used, respectively), and over 80 % of patients requested additional help for their OAB symptoms, irrespective of how many anticholinergics were attempted. CONCLUSION: UI symptom burden and adherence to therapy did not change as patients attempted more anticholinergic therapies. These results suggest that for patients who remain incontinent after attempting an anticholinergic, cycling on additional anticholinergics may not provide any additional benefit, resulting in sub-optimal care.

Health Resource Utilization and Cost for Patients with Incontinent Overactive Bladder Treated with Anticholinergics.

BACKGROUND: Overactive bladder (OAB) is a common medical condition with significant economic and humanistic burden. Inadequately managed OAB may exacerbate or result in comorbidities such as depression, falls, and urinary tract infections, which can further increase the burden to the health care system. Anticholinergics are often prescribed for management of OAB with urinary incontinence ("wet" OAB). However, research has shown that patient adherence and persistence to anticholinergic therapy is poor, with approximately 80% of patients ultimately failing their first prescribed anticholinergic medication within the first year. While there has been a fair amount of research on the economic burden of OAB, the real-world impact of initiating anticholinergic therapy in patients with wet OAB has not been well studied. OBJECTIVE: To compare falls/fractures, anxiety/depression, health care resource utilization, and health care costs between a cohort of patients with wet OAB who initiated anticholinergic therapy and a matched cohort of patients without OAB. METHODS: This study was a retrospective medical and pharmacy claims analysis. Cases were members of a primary care-based, multispecialty physician medical group located in California. Cases were eligible for inclusion if they were prescribed anticholinergic therapy between January 2008 and May 2012 based on pharmacy claims, had a diagnosis of OAB, and reported having ≥ 1 urinary incontinence episode per day. Wet OAB cases were matched to non-OAB controls in a 1:3 ratio based on sex, age, and observation time. Medical and pharmacy claims data were used to analyze patient comorbidities, as well as track health care resource utilization (HRU) and direct payer costs. RESULTS: After initiating anticholinergic therapy, wet OAB patients had a 46% higher adjusted risk of experiencing falls/fractures (P < 0.001) and a 33% higher adjusted risk of experiencing depression/anxiety (P = 0.022) than non-OAB patients. Wet OAB was significantly associated with increased HRU rates of hospital admissions, outpatient visits, prescriptions filled, and diagnostic tests performed. After adjustment for covariates, total health care cost was 33% higher for wet OAB patients than non-OAB patients, resulting in an increased cost of $1,746 per member per year. CONCLUSIONS: The findings of this research suggest OAB patients who initiate anticholinergic therapy and still experience incontinence are at a greater risk for comorbidities such as falls/fractures and depression/anxiety, and use significantly more health care resources, than patients without OAB. Programs to improve patient monitoring and referrals, the appropriate use of alternative treatments within guidelines, and adherence to evidence-based practice parameters may improve clinical outcomes and decrease HRU for these patients. DISCLOSURES: This study was sponsored by Allergan, Irvine, California, which reviewed and approved the final manuscript. At the time of the study, Yehoshua had received a fellowship at the University of Arizona, which was funded by Allergan. Yehoshua, Joshi, and Campbell are employees of Allergan. Vasaveda has received consulting fees from Allergan, Medtronic, and Boston Scientific. Chancelor has received consulting fees from Allergan and Medtronic. All authors met the ICMJE authorship criteria. Neither honoraria nor payments were made for authorship. Study design was created by Yehoshua, Pulicharam, Malone, and Armstrong. Pulicharam took the lead in data collection, along with Chancellor and Campbell, and data interpretation was performed by Chancellor, Vasavada, Malone, and Armstrong. The manuscript was written by Yehoshua and revised by Joshi and Yehoshua, with assistance from the other authors.