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Background: TP53 mutations are associated with an adverse prognosis in acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes (HR-MDS). However, the integrated genetic, epigenetic, and immunologic landscape of TP53 -mutated AML/HR-MDS is not well defined. Objectives: To define the genetic, epigenetic, and immunologic landscape of TP53- mutant and TP53 wild-type AML and HR-MDS patients. Design: Post hoc analysis of TP53- mutant and TP53 wild-type patients treated on the randomized FUSION trial with azacitidine ± the anti-PD-L1 antibody durvalumab. Methods: We performed extensive molecular, epigenetic, and immunologic assays on a well-annotated clinical trial dataset of 61 patients with TP53- mutated disease (37 AML, 24 MDS) and 144 TP53 wild-type (89 AML, 55 MDS) patients, all of whom received azacitidine-based therapy. A 38 gene-targeted myeloid mutation analysis from screening bone marrow (BM) was performed. DNA methylation arrays, immunophenotyping and immune checkpoint expression by flow cytometry, and gene expression profiles by bulk RNA sequencing were assessed at baseline and serially during the trial. Results: Global DNA methylation from peripheral blood was independent of TP53 mutation and allelic status. AZA therapy led to a statistically significant decrease in global DNA methylation scores independent of TP53 mutation status. In BM from TP53- mutant patients, we found both a higher T-cell population and upregulation of inhibitory immune checkpoint proteins such as PD-L1 compared to TP53 wild-type. RNA sequencing analyses revealed higher expression of the myeloid immune checkpoint gene LILRB3 in TP53- mutant samples suggesting a novel therapeutic target. Conclusion: This integrated analysis of the genetic, epigenetic, and immunophenotypic landscape of TP53 mutant AML/HR-MDS suggests that differences in the immune landscape resulting in an immunosuppressive microenvironment rather than epigenetic differences contribute to the poor prognosis of TP53- mutant AML/HR-MDS with mono- or multihit TP53 mutation status. Trial registration: FUSION trial (NCT02775903).

Abstract Notable treatment advances have been made in recent years for patients with myelodysplastic syndromes/neoplasms (MDS), and several new drugs are under development. For example, the emerging availability of oral MDS therapies holds the promise of improving patients' health‐related quality of life (HRQoL). Within this rapidly evolving landscape, the inclusion of HRQoL and other patient‐reported outcomes (PROs) is critical to inform the benefit/risk assessment of new therapies or to assess whether patients live longer and better, for what will likely remain a largely incurable disease. We provide practical considerations to support investigators in generating high‐quality PRO data in future MDS trials. We first describe several challenges that are to be thoughtfully considered when designing an MDS‐focused clinical trial with a PRO endpoint. We then discuss aspects related to the design of the study, including PRO assessment strategies. We also discuss statistical approaches illustrating the potential value of time‐to‐event analyses and their implications within the estimand framework. Finally, based on a literature review of MDS randomized controlled trials with a PRO endpoint, we note the PRO items that deserve special attention when reporting future MDS trial results. We hope these practical considerations will facilitate the generation of rigorous PRO data that can robustly inform MDS patient care and support treatment decision‐making for this patient population.

Abstract Background Brain pericytes participate in the regulation of cerebral blood flow and the maintenance of blood–brain barrier integrity. Because of their perivascular localization, their receptor repertoire, and their potential ability to respond to inflammatory and infectious stimuli by producing various cytokines and chemokines, these cells are also thought to play an active role in the immune response to brain infections. This assumption is mainly supported by in vitro studies, investigations in in vivo disease models are largely missing. Here, we analysed the role of brain pericytes in pneumococcal meningitis, in vitro and in vivo in two animal models of pneumococcal meningitis. Methods Primary murine and human pericytes were stimulated with increasing concentrations of different serotypes of Streptococcus pneumoniae in the presence or absence of Toll-like receptor inhibitors and their cell viability and cytokine production were monitored. To gain insight into the role of pericytes in brain infection in vivo, we performed studies in a zebrafish embryo model of pneumococcal meningitis in which pericytes were pharmacologically depleted. Furthermore, we analyzed the impact of genetically induced pericyte ablation on disease progression, intracranial complications, and brain inflammation in an adult mouse model of this disease. Results Both murine and human pericytes reacted to pneumococcal exposure with the release of selected cytokines. This cytokine release is pneumolysin-dependent, TLR-dependent in murine (but not human) pericytes and can be significantly increased by macrophage-derived IL-1b. Pharmacological depletion of pericytes in zebrafish embryos resulted in increased cerebral edema and mortality due to pneumococcal meningitis. Correspondingly, in an adult mouse meningitis model, a more pronounced blood–brain barrier disruption and leukocyte infiltration, resulting in an unfavorable disease course, was observed following genetic pericyte ablation. The degree of leukocyte infiltration positively correlated with an upregulation of chemokine expression in the brains of pericyte-depleted mice. Conclusions Our findings show that pericytes play a protective role in pneumococcal meningitis by impeding leukocyte migration and preventing blood–brain barrier breaching. Thus, preserving the integrity of the pericyte population has the potential as a new therapeutic strategy in pneumococcal meningitis.

About 10% of newly diagnosed and 20–30% of therapy-related acute myeloid leukemia (AML) harbors a TP53 mutation (mTP53-AML). Unfortunately, this biological subset predicts one of the worst prognoses among patients with AML, specifically a median overall survival of about 7 months with fewer than 10% of patients eventually cured of disease. Although remission rates appear to be increased with venetoclax-based, less-intensive regimens when compared with contemporary, intensive chemotherapy (55–65% vs. 40%), survival appears to be no different between the two approaches. Attempts to discern whether or not the prognosis of mTP53-AML is universally poor have centered around the study of concurrent cytogenetic risk and predicted TP53 allelic state, measurable residual disease status and the impact of conditioning intensity for patients proceeding to allogeneic hematopoietic stem cell transplantation. We discuss these considerations in this review and offer the current treatment approach to TP53-mutated AML.

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis with peripheral blood cytopenias, dysplastic cell morphology, and a variable risk of progression to acute myeloid leukemia (AML). The hypomethylating agents (HMA) azacitidine and decitabine have been used for over a decade in MDS treatment and lead to a modest survival benefit. However, response rates are only around 40% and responses are mostly transient. For HMA-refractory patients the prognosis is poor and there are no therapies approved by the United States Food and Drug Administration. Combinations of HMAs, especially along with immune checkpoint inhibitors, have shown promising signals in both the frontline and HMA-refractory setting. Several other novel agents including orally available and longer acting HMAs, the BCL-2 inhibitor venetoclax, oral agents targeting driver mutations ( IDH1/2, FLT3 ), immunotherapies, and new options for intensive chemotherapy have been studied with variable success and will be reviewed herein. Except for the minority of patients with targetable driver mutations, HMAs – likely as part of combination therapies – will remain the backbone of frontline MDS treatment. However, the wider use of genetic testing may enable a more targeted and individualized therapy of MDS patients.

Immunosuppressive therapy (IST) is one therapy option for treatment of patients with lower-risk myelodysplastic syndromes (MDS). However, the use of several different immunosuppressive regimens, the lack of high-quality studies, and the absence of validated predictive biomarkers pose important challenges. We conducted a systematic review and meta-analysis according to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and searched MEDLINE via PubMed, Ovid EMBASE, COCHRANE registry of clinical trials (CENTRAL), and the Web of Science without language restriction from inception through September 2018, as well as relevant conference proceedings and abstracts, for prospective cohort studies or clinical trials investigating IST in MDS. Fixed and Random-effects models were used to pool response rates. We identified nine prospective cohort studies and 13 clinical trials with a total of 570 patients. Overall response rate was 42.5% [95% confidence interval (CI): 36.1-49.2%] including a complete remission rate of 12.5% (95%CI: 9.3-16.6%) and red blood cell transfusion independence rate of 33.4% (95% CI: 25.1–42.9%). The most commonly used forms of IST were anti-thymocyte globulin alone or in combination with cyclosporin A with a trend towards higher response rates with combination therapy. Progression rate to acute myeloid leukemia was 8.6% per patient year (95%CI: 3.3-13.9%). Overall survival and adverse events were only inconsistently reported. We were unable to validate any biomarkers predictive of a therapeutic response to IST. IST for treatment of lower-risk MDS patients can be successful to alleviate transfusion burden and associated sequelae.

The LEADERS FREE trial concluded that the polymer free drug-coated BioFreedom™ stent appeared to be both safer and more effective than bare-metal stents (BMS) with an ISR rate comparable to traditional DES without the need for prolonged DAPT. We implanted 45 BioFreedom™ stents in 34 patients over a 4-month period. 4 patients represented early (106–238 days after the implant procedure) with angina symptoms and severe ISR was detected in all patients. The rate of severe and early ISR detected in our patient population of 11.8% is comparable to that of traditional BMS. Further studies are warranted.

Abstract Background In a world of ever increasing health care costs, generic drugs represent a major opportunity to ensure access to essential medicines for people who otherwise would be unable to afford them. However, some clinicians and patients are still questioning the safety and effectiveness of generic formulations compared to the proprietary drugs necessitating further systematic research analyzing the generic drugs’ efficacy. Our objective was to compare the lipid lowering effects of generic and branded atorvastatin. Methods This cross-sectional, retrospective cohort study was conducted at the University of Malaya Medical Centre from 1 May 2013 until 30 May 2013. We analyzed the lipid profiles (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides) of 629 patients before and at least 3 months after switching them from proprietary atorvastatin (Lipitor®) to generic atorvastatin (atorvastatin calcium from Ranbaxy Laboratories, Inc.). We also investigated if there was any difference in the effectiveness of both atorvastatin formulations in various ethnic groups. Results 266 patients were included in this study. When comparing the median values we found no statistically significant differences (Wilcoxon signed-rank test; p

Epigenetics refers to the regulation of gene expression mainly by changes in DNA methylation and modifications of histone proteins without altering the actual DNA sequence. While epigenetic modifications are essential for normal cell differentiation, several driver mutations in leukemic pathogenesis have been identified in genes that affect epigenetic processes, such as DNA methylation and histone acetylation. Several therapeutic options to target epigenetic alterations in acute myeloid leukemia (AML) have been successfully tested in preclinical studies and various drugs have already been approved for use in clinical practice. Among these already approved therapeutics are hypomethylating agents (azacitidine and decitabine) and isocitrate dehydrogenase inhibitors (ivosidenib, enasidenib). Other agents such as bromodomain-containing epigenetic reader proteins and histone methylation (e.g. DOT1L) inhibitors are currently in advanced clinical testing. As several epigenetic therapies have only limited efficacy when used as single agents, combination therapies that target AML pathogenesis at different levels and exploit synergistic mechanisms are also in clinical trials. Combinations of either epigenetic therapies with conventional chemotherapy, different forms of epigenetic therapies, or epigenetic therapies with immunotherapy are showing promising early results. In this review we summarize the underlying pathophysiology and rationale for epigenetically-based combination therapies, review current preclinical and clinical data and discuss the future directions of epigenetic therapy combinations in AML.

Nearly four decades after their conceptualization, antibody-based therapies are slowly being added to the treatment landscape of acute myeloid leukemia (AML). While the antibody–drug conjugate gemtuzumab ozogamicin is the only antibody-based therapy that has been approved for AML treatment thus far, several bispecific antibodies have been developed and shown early encouraging results. Bispecific antibodies comprise a wide variety of constructs that share the common concept of simultaneous binding of a surface target on malignant cells and most commonly CD3 on T cells leading to an endogenous, HLA-independent, immune response against malignant cells. However, the use of bispecific antibodies in AML has been limited by the absence of highly specific leukemia-associated antigens leading to on-target, off-leukemia side effects as well as reduced efficacy due to antigen escape. Herein, we discuss the history and evolution of bispecific T cell engagers as well as various adaptations such as dual affinity retargeting antibodies, bi- and tri-specific killer engager antibodies. Common side effects including cytokine release syndrome and management thereof are highlighted. Lastly, we expound on the future direction and integration of such antibody-based therapies with other immunotherapies (programmed cell death-1 inhibitors and chimeric antigen receptor T cells).

Up to 18% of patients with acute myeloid leukemia (AML) present with a white blood cell (WBC) count of greater than 100,000/µL, a condition that is frequently referred to as hyperleukocytosis. Hyperleukocytosis has been associated with an adverse prognosis and a higher incidence of life-threatening complications such as leukostasis, disseminated intravascular coagulation (DIC), and tumor lysis syndrome (TLS). The molecular processes underlying hyperleukocytosis have not been fully elucidated yet. However, the interactions between leukemic blasts and endothelial cells leading to leukostasis and DIC as well as the processes in the bone marrow microenvironment leading to the massive entry of leukemic blasts into the peripheral blood are becoming increasingly understood. Leukemic blasts interact with endothelial cells via cell adhesion molecules such as various members of the selectin family which are upregulated via inflammatory cytokines released by leukemic blasts. Besides their role in the development of leukostasis, cell adhesion molecules have also been implicated in leukemic stem cell survival and chemotherapy resistance and can be therapeutically targeted with specific inhibitors such as plerixafor or GMI-1271 (uproleselan). However, in the absence of approved targeted therapies supportive treatment with the uric acid lowering agents allopurinol and rasburicase as well as aggressive intravenous fluid hydration for the treatment and prophylaxis of TLS, transfusion of blood products for the management of DIC, and cytoreduction with intensive chemotherapy, leukapheresis, or hydroxyurea remain the mainstay of therapy for AML patients with hyperleukocytosis.

Mast cells reside on and near the cerebral vasculature, the predominant site of pneumococcal entry into the central nervous system (CNS). Although mast cells have been reported to be crucial in protecting from systemic bacterial infections, their role in bacterial infections of the CNS remained elusive. Here, we assessed the role of mast cells in pneumococcal infection in vitro and in vivo. In introductory experiments using mouse bone marrow-derived mast cells (BMMC), we found that (i) BMMC degranulate and release selected cytokines upon exposure to Streptococcus pneumoniae, (ii) the response of BMMC varies between different pneumococcal serotypes and (iii) is dependent on pneumolysin. Intriguingly though, apart from a slight enhancement of cerebrospinal fluid (CSF) pleocytosis, neither two different mast cell-deficient Kit mutant mouse strains (WBB6F1-KitW/Wv and C57BL/6 KitW-sh/W-sh mice) nor pharmacologic mast cell stabilization with cromoglycate had any significant impact on the disease phenotype of experimental pneumococcal meningitis. The incomplete reversal of the enhanced CSF pleocytosis by local mast cell engraftment suggests that this phenomenon is caused by other c-Kit mutation-related mechanisms than mast cell deficiency. In conclusion, our study suggests that mast cells can be activated by S. pneumoniae in vitro. However, mast cells do not play a significant role as sentinels of pneumococcal CSF invasion and initiators of innate immunity in vivo.