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.

Measuring the Impact of Nonignorable Missingness Using the R Package isni.

BACKGROUND AND OBJECTIVE: The popular assumption of ignorability simplifies analyses with incomplete data, but if it is not satisfied, results may be incorrect. Therefore it is necessary to assess the sensitivity of empirical findings to this assumption. We have created a user-friendly and freely available software program to conduct such analyses. METHOD: One can evaluate the dependence of inferences on the assumption of ignorability by measuring their sensitivity to its violation. One tool for such an analysis is the index of local sensitivity to nonignorability (ISNI), which evaluates the rate of change of parameter estimates to the assumed degree of nonignorability in the neighborhood of an ignorable model. Computation of ISNI avoids the need to estimate a nonignorable model or to posit a specific magnitude of nonignorability. Our new R package, named isni, implements ISNI analysis for some common data structures and corresponding statistical models. RESULT: The isni package computes ISNI in the generalized linear model for independent data, and in the marginal multivariate Gaussian model and the linear mixed model for longitudinal/clustered data. It allows for arbitrary patterns of missingness caused by dropout and/or intermittent missingness. Examples illustrate its use and features. CONCLUSIONS: The R package isni enables a systematic and efficient sensitivity analysis that informs evaluations of reliability and validity of empirical findings from incomplete data.

TA205, an anti-talin monoclonal antibody, inhibits integrin-talin interaction.

Talin mediates integrin signaling by binding to integrin cytoplasmic tails through its FERM domain which consists of F1, F2 and F3 subdomains. TA205, an anti-talin monoclonal antibody, disrupts actin stress fibers and focal adhesion when microinjected into fibroblasts. Here, we showed that TA205 caused an allosteric inhibition of integrin alphaIIb beta3 binding to the talin FERM domain and mapped the TA205 epitope to residues 131-150 in talin F1. Furthermore, binding of a talin rod fragment to talin head was partially inhibited by TA205. These findings suggest that talin F1 may be important in regulation of integrin binding and talin head-rod interaction.

Purification and Characterization of the Fibrinolytic Enzyme(eFE-D) from Earthworm Eisenia folelide.

The fibrinolytic enzyme eFE-D was isolated and purified from earthworm Elsenia folelide by gel-filtration on Sephacryle S-200, ion-exchange chromatography on DEAE-Sepharose Fast Flow and hydrophobic chromatography on Phenyle-Sepharose Fast Flow as detected by the fibrinolytic activity with a standard fibrin plate method. The most strong fibrinolytic component eFE-D not only hydrolyzed fibrin directly, but also activated the plasminogen to plasmin. Its apparent fibrinolytic value was equal to 2,800 UK IU per mg. Its molecular weight as estimated by SDS-PAGE and MS analysis was 29 kD and 24.849 kD respectively and its isoelectric point (pI) was 4.O. Fibrinolytic enzyme eFE-D was very thermostable with a single polypeptide chain. Studies with protease inhibitors indicated that eFE-D was a kind of serine protease. Its N-terminal amino acid sequence is M-I-G-G-T-N-A-S-P-G-E-F-P-W-Q-L-S-Q-Q-R. The result of amino acid composition analysis showed that the enzyme contained abundant amino acids of low molecular weight, but few aromatic and alkaline amino acids.