Altered Serum Alpha1-Antitrypsin Protease Inhibition before and after Clinical Hematopoietic Stem Cell Transplantation: Association with Risk for Non-Relapse Mortality.

α1-Antitrypsin (AAT), an acute-phase reactant not unsimilar to C-reactive protein (CRP), is a serine protease inhibitor that harbors tissue-protective and immunomodulatory attributes. Its concentrations appropriately increase during conditions of extensive tissue injury, and it induces immune tolerance, in part, by inhibiting the enzymatic activity of the inflammatory serine protease, proteinase 3 (PR3). Typically administered to patients with genetic AAT deficiency, AAT treatment was recently shown to improve outcomes in patients with steroid-refractory graft-versus-host disease (GVHD). GVHD represents a grave outcome of allogeneic hematopoietic stem cell transplantation (HSCT), a potentially curative intervention for hematological diseases. The procedure requires radio/chemotherapy conditioning of the prospective marrow recipient, a cytotoxic process that causes vast tissue injury and, in some formats, interferes with liver production of AAT. To date, changes in the functional profile of AAT during allogeneic HSCT, and during the cytotoxic intervention that precedes HSCT, are unknown. The present study followed 53 patients scheduled for allogeneic HSCT (trial registration NCT03188601). Serum samples were tested before and after HSCT for AAT and CRP levels and for intrinsic anti-proteolytic activity. The ex vivo response to clinical-grade AAT was tested on circulating patient leukocytes and on a human epithelial cell line treated with patient sera in a gap closure assay. According to the ex vivo experiments, circulating leukocytes responded to AAT with a favorable immune-regulated profile, and epithelial gap closure was enhanced by AAT in sera from GVHD-free patients but not in sera from patients who developed GVHD. According to serum collected prior to HSCT, non-relapse mortality was reliably predicted by combining three components: AAT and CRP levels and serum anti-proteolytic activity. Taken together, HSCT outcomes are significantly affected by the anti-proteolytic function of circulating AAT, supporting early AAT augmentation therapy for allogeneic HSCT patients.

Post-transplantation maintenance with sorafenib or midostaurin for FLT3 positive AML patients - a multicenter retrospective observational study.

The role of post allogeneic stem-cell transplantation (AlloSCT) FLT3 inhibition for acute myeloid leukemia in the real-world setting is unclear, especially in the era of widespread pre-transplant use of tyrosine kinase inhibitors (TKIs). In a multicenter nationwide study, we assessed 41 patients who were treated with post-transplant TKIs (sorafenib, n = 23, midostaurin, n = 18). The majority also received TKIs pre-transplant (n = 32, 79%). After a median follow up of 10 months post-transplant (range 3-53.6), 29 patients (71%) were alive and in complete remission. Similar results were seen in a subgroup analysis of pre-transplant TKI recipients (78%). In Univariate analysis, HCT-CI score < 4 and Type of TKI (sorafenib versus midostaurin) predicted longer overall survival. Seventeen patients (41%) suffered from side effects and seven patients (17%) stopped TKI therapy due to adverse events. Overall, our data suggest that post-transplant use of TKIs is safe and effective in an era of their widespread use prior to AlloSCT.

Venetoclax is safe and efficacious in relapsed/refractory AML.

Data from 11 Israeli centers, where venetoclax was used for relapsed/refractory AML after intensive chemotherapy, were retrospectively collected. During 2016-2019, forty patients were identified. Median age was 67 years (21-82), 60% males, median of 2(1-4) prior lines of treatment and 42% relapsed after allogeneic transplant. 62.5% of the patients received the venetoclax with hypomethylating agents and 22.5% with low dose cytarabine. Median follow-up was 5.5 months. Of the 29 patients who survived for more than two cycles of therapy, 22 (76%) achieved neutrophil recovery and 59% (n = 17) recovered also their platelet count. In 15 (52% of those who survived > 2 months), CR/CRi was confirmed by bone marrow examination. The median OS from venetoclax initiation of all the patients and of those who survived more than 2 months was 5.5 and 6.5 months, respectively. In conclusion, this study demonstrates that venetoclax is safe and active also in AML patients with advanced disease.

Recovery attributions: explicit endorsement of biomedical factors and implicit dominance of psycho-social factors.

Two studies assessed lay people's bio-medical and psycho-social attributions for recovery, using implicit and explicit methods, and one of them, Study 2, also measured individual differences in health locus of control. Participants were presented with a vignette of a patient with a severe disease for which chances of recovery vary widely, who had high or low levels of medical care and high or low psycho-social resources. They estimated his chances to recover from his illness (implicit attributions), and then, imagining another patient with the same disease, evaluated the relative importance of medical, psycho-social and other factors for his chances for recovery (explicit method). Findings show a moderation effect by assessment method: the explicit method pointed to dominance of biomedical attributions and the implicit method indicated dominance of psycho-social attributions. In addition, internal health locus of control was positively correlated with psycho-social attributions and external health locus of control (powerful others and chance) was correlated with biomedical attributions for recovery. The findings are discussed in relation to dual-process models of reasoning and self-serving defensive processes.