A phase 2a randomized clinical trial of intravenous vedolizumab for the treatment of steroid-refractory intestinal acute graft-versus-host disease

Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) remains a significant complication after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are first-line therapy for aGvHD, but apart from ruxolitinib, there are no approved treatments for SR aGvHD. Vedolizumab is approved for treatment of ulcerative colitis and Crohn\u27s disease, and may be effective for treatment of SR intestinal aGvHD. We conducted a phase 2a trial (NCT02993783) to evaluate the clinical efficacy, tolerability, and safety of vedolizumab 300 and 600 mg for SR intestinal aGvHD. This study was terminated before full enrollment was completed because early results failed to demonstrate positive proof-of-concept in efficacy. Before termination, 17 participants had enrolled and an early response in intestinal aGvHD was observed in 11 and eight participants at days 15 and 28, respectively. All adverse events observed were consistent with those expected in a population with SR intestinal aGvHD. Overall, vedolizumab did not meet the primary efficacy endpoint (overall response at day 28), likely owing to premature study drug discontinuation, lack of efficacy, and the competing risks inherent with a population with advanced SR intestinal aGvHD. Nevertheless, this study provides valuable insights into the considerations needed when conducting studies in patients with SR intestinal aGvHD

An Early Biomarker Algorithm Predicts Lethal Graft-Vs-Host Disease and Survival after Allogeneic Hematopoietic Cell Transplantation

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Biomarkers Predict Graft-Vs-Host Disease Outcomes Better Than Clinical Response after One Week of Treatment

Abstract Graft-versus-host disease (GVHD), the primary cause of non-relapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation, does not always respond to treatment with high dose systemic corticosteroids. We have recently shown that a combination of three biomarkers (TNFR1, ST2, and REG3α) measured at onset of GVHD can predict day 28 response to treatment and 6-month NRM (Levine, Lancet Haem, 2015). Our goal in the current study was to determine if the same biomarker-based Ann Arbor GVHD algorithm can alsopredict treatment response andmortality whenapplied after one week of systemic corticosteroid treatment. The study population consisted of 378 patients (pts) with acute GVHD from 11 centers in the Mount Sinai Acute GVHD International Consortium. All pts were treated with systemic steroids and provided a plasma or serum sample obtained after one week of treatment (±3 days). The median starting dose of systemic steroids for Grade II-IV GVHD was 2.0 mg/kg/day and for Grade I was 1.0 mg/kg/day, after which treatment varied. Patients were divided into test (n=236) and validation (n=142) cohorts. We applied the Ann Arbor GVHD algorithm to concentrations of TNFR1, ST2, and REG3α measured after one week of treatment to generate a predicted probability of 6-month NRM, which we term the treatment score (TS). We employed unsupervised k-medoidclustering to partition TS values from the test cohort into two groups (high and low). This unbiased approach identified a high score group made up of 25% of pts (n=58) in the test cohort. We observed that the day 28 response rate (complete, CR + partial, PR) was significantly lower in pts with high scores compared to low scores in the test cohort (24% vs 65%, p<0.0001) (Fig 1A). Analysis of the validation cohort using the same TS definitions showed similar differences in response rates (22% vs 61%, p<0.0001) (Fig 1B). Further, nearly four times as many pts with high scores in both cohorts died within 6 months from non-relapse causes compared to pts with low scores (test: 57% vs 17%, p<0.0001; validation: 57% vs 14%, p<0.0001) (Fig 1C/D). As expected, the majority of non-relapse deaths in pts treated for GVHD were directly attributable to GVHD (test: 95%; validation: 89%). Relapse rates for high and low score pts were similar (data not shown), and thus pts with a high TS experienced significantly worse overall survival in both cohorts (test: 37% vs 72%, p<0.0001; validation: 38% vs 79%, p<0.0001) (Fig 1E/F). Approximately half of the pts in each cohort (test: 48%; validation: 44%) responded (CR+PR) to the first week of steroids and these ptshad significantly lower 6-month NRM than non-responders (NR) (test: 17% vs 36%, p=0.0002; validation: 13% vs 36%, p=0.0014). Yet the TS continued to stratify mortality risk independently of clinical response. In the test cohort, pts with a high score comprised 16% of all early responders and experienced more than twice the NRM of early responders with a low score (33% vs 13%, p=0.022) (Fig 2A). Conversely, test cohort pts who did not respond by day 7, but had a low score, fared much better than non-responders with a high score (NRM 21% vs 68%, p<0.0001) (Fig 2B). Two thirds of early non-responders comprised this more favorable group. These highly significant results reproduced in the independent validation cohort in similar proportions (CR+PR: 45% vs 6%, p=0.0003; NR: 61% vs 22%, p=0.0001) (Fig 2C/D). Finally, a subset analysis revealed that pts classified as NR after one week of steroids due to isolated, yet persistent, grade I skin GVHD (24/378, 6%) overwhelmingly had low treatment scores (22/24, 92%) and experienced rates of NRM (9%) comparable to responders with low scores, thus forming a distinct, albeit small, subset of pts with non-responsive GVHD that fares particularly well (Fig 3). In conclusion, a treatment score based on three GVHD biomarkers measured after one week of steroids stratifies pts into two groups with distinct risks for treatment failure and 6-month NRM. It is particularly noteworthy that the TS identifies two subsets of pts with steroid refractory (SR) GVHD who have highly different outcomes (Fig 2B/D). The much larger group, approximately two thirds of all SR pts, may not need the same degree of treatment escalation as is traditional for clinical non-response, and thus overtreatment might be avoided. Because the TSis measured at a common decision making time point, it may prove useful to guide risk-adapted therapy. Disclosures Mielke: Novartis: Consultancy; MSD: Consultancy, Other: Travel grants; Celgene: Other: Travel grants, Speakers Bureau; Gilead: Other: Travel grants; JAZZ Pharma: Speakers Bureau. Kroeger:Novartis: Honoraria, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Jagasia:Therakos: Consultancy. Kitko:Therakos: Honoraria, Speakers Bureau. Ferrara:Viracor: Patents & Royalties: GVHD biomarker patent. Levine:Viracor: Patents & Royalties: GVHD biomarker patent

Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

Bioabsorption and Effectiveness of Long-Lasting Permethrin-Treated Uniforms Over Three Months Among North Carolina Outdoor Workers

Abstract Background Vector-borne diseases are an important cause of morbidity and mortality in the USA. Effective, convenient prevention methods are needed. Long-lasting permethrin-impregnated (LLPI) clothing can prevent tick bites, however, additional information is needed on the real-world effectiveness and safety of this preventative measure. Methods In this pilot study, we recruited state and county park employees from North Carolina to wear LLPI uniforms for three months during the summer of 2016. We collected spot urine samples for biomonitoring of permethrin metabolites at one week, one month and three months after first use of the LLPI uniform. Following three months of wear, we collected pants and socks and analyzed them for permethrin content and mortality to ticks and mosquitoes. Results Thirteen park employees were included in the analysis. Bioactive amounts of permethrin remained in all clothing swatches tested, although there was great variability. Tick mortality was high, with 78% of pant and 88% of sock swatches having mean knockdown percentages ≥ 85%. In contrast, mosquito mortality was low. Over the study period, the absorbed dosage of permethrin averaged < 4 μg/kg/d of body weight based on measurements of three metabolites. Conclusions LLPI clothing retained permethrin and bioactivity against ticks after three months of use in real-world conditions. The estimated absorbed dosage of permethrin was well below the U.S. EPA level of concern, suggesting that LLPI clothing can be used safely by outdoor workers for tick bite prevention

Allogeneic Transplantation for Acute Leukemias

Allogeneic Transplantation for Acute Leukemias, Anne Renteria, M.D., Medical Director, Bone Marrow Transplant, Lipson Cancer and Blood Center | Lipson Cancer Institute. Topics: Current practice Historical perspective Guiding principles Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Allo-HCT outcomes in AML Future direction

Autologous Transplantation and CAR-T Cell Therapies for Lymphomas

Department Meeting: What\u27s the GFR? Removing the Social Construct of Race from Estimates of Kidney Function, Drs. Marvin Grieff, Chris Reynolds, Roberto Vargas Case Presentation: Autologous Transplantation and CAR-T Cell Therapies for LymphomasAgenda: Case Presentation Diffuse Large B-Cell Lymphoma Autologous Transplantation for Lymphoma CAR-T Therap

Protecting Possession, a Question of Values? A Comparative Inquiry into the Moralization of Possession in Brazil and Canada

This paper focuses on possessory protection of immovables (or real property) in Brazilian civil law and Canadian common law. In both jurisdictions, possession enjoys a specific protection or status, which in turn relates to the rest of property law, particularly the law of acquisitive prescription, in a specific way. But in and by itself, despite these conceptual differences, possessory protection in Canada or Brazil works in an objective fashion: it is not denied to possessors in bad faith as a principle. Nonetheless, in both systems, the institutions designed to protect possession have been “moralized” by judges to echo concerns similar to those voiced in relation to acquisitive prescription, but also to emphasize human rights, constitutional values and good faith. In Brazil, this moralization process is the consequence of the emergence of a constitutionalized civil law and of the social function of the right of ownership. In several cases, it has allowed illicit buildings to remain where they are despite the owner’s claim, for instance when a favela has appeared on a land neglected by its owner for years. In England, the possessor’s good faith has been scrutinized through his intent to possess, and under the lenses of the future enjoyment criteria, later rejected by the Court of Appeal. In Canada, the test of the inconsistent use of the land has played the same moralizing role and continues to do so, to deny the benefit of adverse possession to squatters and to prevent them from enjoying possessory protection.Le présent article compare la protection possessoire des immeubles en droit civil brésilien et en common law canadienne. Dans chacun de ces systèmes, la possession commande une protection et un statut particuliers, qui s’arriment au reste du droit des biens, et particulièrement celui gouvernant la prescription acquisitive, d’une manière distincte. Mais en elle-même, la protection possessoire au Canada et au Brésil fonctionne de manière objective, donc y compris au bénéfice des possesseurs de mauvaise foi. Cependant, de part et d’autre, la protection possessoire a fait l’objet d’un processus de moralisation par les juges, de façon à faire écho à des préoccupations traditionnellement associées à la prescription acquisitive, mais aussi aux droits de la personne, aux valeurs constitutionnelles et à la bonne foi. Au Brésil, cette « moralisation » est la conséquence de l’émergence d’un droit civil constitutionnel et de la fonction sociale du droit de propriété. En plusieurs instances, elle a permis le maintien de favelas localisées sur le terrain d’autrui, lorsque le propriétaire du fond était demeuré passif devant l’intrusion pendant une longue période. En Angleterre, la bonne foi du possesseur est examinée à la lumière de son intention de posséder et du critère de la jouissance future, finalement rejeté par la Cour d’appel. Au Canada, le test de l’usage inconsistant du fonds continue de jouer le même rôle : dénier le bénéfice de la possession adversative aux « squatters » et les empêcher de se prévaloir de la protection possessoire

AML with BCR-ABL1 Fusion treated with Imatinib, a Hypomethylating Agent and Venetoclax

A patient with history of myelodysplastic syndrome (MDS) presented with multifocal pneumonia and was found to have Philadelphia chromosomepositive (Ph+) acute myeloid leukemia (AML). A tyrosine kinase inhibitor (TKI) was added to decitabine and venetoclax combination, providing a molecular and cytogenetic complete response despite additional cytogenetic and molecular abnormalities. She remains in remission after eleven cycles of treatment. Our report describes the tolerability and success of a triplet regimen that incorporates a TKI to a backbone of decitabine and venetoclax in a patient with high-risk disease and with significant comorbidities