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.

Comparative analysis of tabelecleucel and current treatment in patients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease following hematopoietic cell transplant or solid organ transplant.

AIMS: With recent European Union marketing authorization, tabelecleucel is the first off-the-shelf, allogeneic Epstein-Barr virus (EBV)-specific T-cell immunotherapy approved for the treatment of relapsed/refractory EBV-positive post-transplant lymphoproliferative disease (EBV+ PTLD). In the absence of a control arm, real-world evidence can provide a comparative benchmark for single-arm studies in ultra-rare populations. This study assessed the treatment effect of tabelecleucel in the single-arm phase 3 ALLELE study (NCT03394365) versus a treatment group from a multinational, multicenter retrospective chart review study (RS002) of patients with EBV+ PTLD. METHODS: In ALLELE, patients had disease relapsed/refractory to rituximab ± chemotherapy and received tabelecleucel 2x106 cells/kg on days 1, 8, and 15 in 35-day cycles. Patients in RS002 had disease relapsed/refractory to rituximab ± chemotherapy and received next line of systemic therapy between January 2000 and December 2018. Propensity score-based standardized mortality/morbidity ratio weighting was used to achieve balance between treatment and comparator arms. Kaplan-Meier estimators and Cox regression models were used to compare overall survival (OS) in the re-weighted sample. RESULTS: 30 patients (n = 14 hematopoietic cell transplant [HCT], n = 16 solid organ transplant [SOT]) from ALLELE (data cutoff: November 2021) and 84 patients (n = 36 HCT, n = 48 SOT) from RS002 (data lock: January 2021) were included. Median time from diagnosis to first tabelecleucel dose (ALLELE) or start date of next line of systemic therapy (RS002) was 3.6 months. Tabelecleucel was associated with a substantial OS benefit compared with current treatment, with an unadjusted HR of 0.47 (95% confidence interval [CI] 0.25-0.88) and adjusted HR of 0.37 (95% CI 0.20-0.71) when using the start date of the next line of therapy as the index date. Sensitivity analyses yielded consistent results. CONCLUSIONS: In this study of real-world data, tabelecleucel was associated with an OS benefit among patients with R/R EBV+ PTLD for whom there is high unmet need.

Outcomes for patients with EBV-positive PTLD post-allogeneic HCT after failure of rituximab-containing therapy.

Epstein-Barr virus-positive (EBV+) post-transplant lymphoproliferative disease (PTLD) is an ultra-rare and aggressive condition that may occur following allogeneic hematopoietic cell transplant (HCT) due to immunosuppression. Approximately half of EBV+ PTLD cases are relapsed or refractory (R/R) to initial rituximab-containing therapy. There are limited treatment options and no standard of care for patients with R/R EBV+ PTLD, and little is known about their treatment history and outcomes. We performed a multinational, multicenter, retrospective chart review of patients with R/R EBV+ PTLD following HCT to describe patients' demographic and disease characteristics, treatment history, and overall survival (OS) from rituximab failure. Among 81 patients who received initial treatment with rituximab as monotherapy (84.0%) or in combination with chemotherapy (16.0%), median time from HCT to PTLD diagnosis was 3.0 months and median OS was 0.7 months. Thirty-six patients received a subsequent line of treatment. The most frequent causes of death were PTLD (56.8%), graft-versus-host disease (13.5%) and treatment-related mortality (10.8%). In multivariate analysis, early PTLD onset and lack of response to initial treatment were associated with mortality. This real-world study demonstrates that the prognosis of patients with R/R EBV+ PTLD following HCT remains poor, highlighting the urgent unmet medical need in this population.

Oral white patches in a national sample of medical HIV patients in the era of HAART.

OBJECTIVES: Several types of HIV-related oral mucosal conditions have been reported to occur during the course of HIV disease progression. Of these, few may be manifested as 'white' lesions and many are noticeable to the patient. This paper examines the relationships between social, behavioral and medical aspects of HIV infection and reporting an occurrence of oral white patches (OWP) by HIV-infected patients. METHODS: The subjects are participants in all three interviews in the HIV Cost and Services Utilization Study (HCSUS). The subjects were selected using a three-stage probability sampling design. The multivariate analysis is based on 2109 subjects with nonmissing binary outcome variable for all three waves representing a national sample of 214 000 individuals. The multivariate model was fitted using generalized estimating equations (GEE) by implementing the XTGEE command in STATA. RESULTS: We estimate that 75 000 persons (35%) reported at least one incident of OWP, of these 14 000 reported having OWP during all three interviews, and that the rate of reporting declined over the three HCSUS waves. The multivariate analysis showed seven variables that were significant predictors of at least one report of OWP. CONCLUSIONS: Compared with persons on HAART therapy, patients on other regimens or taking no antiviral medications were 23-46% more likely to report an incident of OWP. Compared with whites, African Americans were 32% less likely to report OWP, while current smokers were 62% more likely than nonsmokers. Being diagnosed with AIDS and having CD4 counts less than 500 significantly increased the likelihood of reporting OWP.

Self-reported satisfaction of enrollees in capitated and fee-for-service dental benefit plans.

BACKGROUND: This article examines the impact of capitated, or CAP, and fee-for-service, or FFS, dental benefit plans on the enrollees' satisfaction with their plans and their satisfaction with their dentists. METHODS: The authors selected four dental markets: California, New Jersey, Michigan and North Carolina. Eight Fortune 500 companies participated. Enrollees were selected randomly and interviewed about their experiences with their dental plans. The sample consisted of 2,340 respondents, of whom 42.3 percent were enrolled in CAP plans and 57.7 percent in FFS plans. RESULTS: The major findings were that those enrolled in FFS plans were four times more likely to be very satisfied than dissatisfied with their dental plans than were those in CAP plans. The FFS plan enrollees were 16 times more likely to be very satisfied than dissatisfied with their dentists than were those in CAP plans. CONCLUSION: Enrollees generally were satisfied with their plans and their dentists but those in FFS plans were the most satisfied. The higher the premium paid, the higher the level of satisfaction. PRACTICE IMPLICATIONS: Enrollees with perceived unmet needs were less satisfied with their dental benefit plans and dentists. Taking care of needs is the most significant thing dentists can do to affect patients' satisfaction.

Self-reported oral health of enrollees in capitated and fee-for-service dental benefit plans.

BACKGROUND: This article examines the impact of different dental plan types, dental markets, premiums, out-of-pocket costs and enrollee demographics on the enrollees' perceived oral health status. METHODS: The authors randomly sampled enrollees in dental benefit plans offered by eight Fortune 500 companies and interviewed them regarding their experiences with their plans, including perceived oral health status. The sample consisted of 2,340 respondents, of whom 42.3 percent were enrolled in capitation, or CAP, plans, and 57.7 percent were enrolled in fee-for-service, or FFS, plans. RESULTS: The authors used chi2 tests, analysis of variance and multinomial logistic regression. They set significance at P < .05. Results indicate that nonwhites, CAP-plan enrollees and those with higher out-of-pocket cost were less likely to rate their oral health "good," "very good" or "excellent" compared with whites, FFS-plan enrollees and those with lower out-of-pocket costs, respectively. CONCLUSIONS: CAP-plan enrollees rated their oral health more poorly than did FFS-plan enrollees. Further studies are necessary to determine if adverse selection occurs and if CAP plans provide inferior quality of care. PRACTICE IMPLICATIONS: Practitioners' awareness of and willingness to address the variety of factors that influence perceived oral health status may improve their patients' perceived oral health status and satisfaction with care.

Experience of Advate rAHF-PFM in previously untreated patients and minimally treated patients with haemophilia A.

We report a prospective trial of 55 previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe/moderately severe haemophilia A (baseline factor VIII [FVIII] ≤2%) treated with a single FVIII replacement product. It was the objective of this study to evaluate the immunogenicity, efficacy, and safety of rAHF-PFM (Advate®). On-demand or prophylactic treatment regimens were determined at the discretion of the investigator. rAHF-PFM was also permitted for perioperative management. There were 633 bleeding episodes (BEs), including 517 treated, and 466 rated for efficacy. Haemostatic efficacy was considered excellent/good in 93% of 466 rated treatments. Of 517 treated BEs, 463/517 (90%) were managed with one (356/517 [69%]) or two infusions (107/517 [21%]). There were 27 surgeries. Intraoperative (n=22) and postoperative (n=25) haemostatic efficacies were considered excellent or good in 100% of rated surgeries. Related serious adverse events (SAEs) were inhibitor development in 16/55 (29.1%) subjects who received at least one infusion of rAHF-PFM. Non-serious, related adverse events (AEs) were few in number (14 in eight subjects). The odds ratio (OR [95% Confidence Interval, CI]) of developing inhibitors was significantly higher in subjects with a family history of inhibitor (4.95[1.29-19.06]), non-Caucasian ethnicity (4.18, [1.18-14.82]), and intensive treatment at high dose (4.5 [1.05-19.25]) within ≤20 exposure days (EDs). In conclusion, rAHF-PFM was safe and effective for the management and perioperative coverage of PUPs/MTPs with severe/moderately severe haemophilia A. This report supports previous findings from studies in which family history of inhibitor, non-Caucasian ethnicity, and high intensity treatment were associated with high risk of inhibitor development.

Characteristics of malt liquor beer drinkers in a low-income, racial minority community sample.

BACKGROUND: The authors describe and compare drinking patterns among malt liquor beer (MLB), regular beer (RB), and hard liquor (HL) drinkers in a low-income, racial/ethnic minority community. METHODS: Drinkers were recruited from randomly selected alcohol outlets in South Los Angeles. Respondents were assessed on sociodemographic characteristics, alcohol use history, drinking patterns, and drinking context among other items in a face-to-face interview with research staff. RESULTS: Three hundred twenty-nine drinkers were interviewed, of whom 297 reported drinking MLB, RB, or HL brands of alcohol most often in the past 90 days. This subsample was 88% African-American, 72% male, and 35% unemployed. As compared with RB and HL drinkers, MLB drinkers were more likely to be homeless, to receive public assistance for housing, and to be unemployed. MLB drinkers also reported significantly higher rates of daily or near-daily drinking (74%, as compared with 48% for RB and 29% for HL) of drinks per day on drinking days (5.2, as compared with 4.2 for RB and 3.1 for HL), and daily average ethanol consumption (6.97 oz, as compared with 2.13 oz for RB drinkers and 6.13 oz for HL drinkers). In multinomial regression analysis that controlled for potential confounders, the odds of preferring RB as compared with MLB were significantly increased among persons with blue-collar occupations and those who reported drinking in public settings and were reduced among persons who drank outdoors, those who combined drinking with tobacco smoking, and those who drank alcohol with members of the same sex. Average daily ethanol consumption odds were reduced for RB drinkers as compared with MLB drinkers. The odds of preferring HL as compared with MLB were significantly increased for persons with white-collar occupations and those who drank in public settings and were reduced for persons who drank outdoors and those who combined drinking and smoking. CONCLUSION: The authors observed substantial differences in sociodemographic characteristics, drinking patterns, and ethanol consumption by beverage type in this community sample. MLB drinkers seem to have distinctive drinking patterns that require additional study to determine whether this pattern is associated with increased individual or community risk.

A longitudinal analysis of unmet need for oral treatment in a national sample of medical HIV patients.

This longitudinal study examines perceived unmet dental need in a nationally representative probability sample of HIV-infected persons in medical care. A logistic regression analysis modeled the relationship between unmet need and explanatory variables. We estimate that 40% of HIV/AIDS patients report an unmet need associated with being male, being unemployed, injecting drugs, being heterosexual, lacking dental insurance, and having less education. Disparities in unmet need are related to socioeconomic status rather than to disease stage or ethnicity.