Venetoclax in combination with nucleoside analogs such as hypomethylating agents (HMA) and low-dose cytarabine (LDAC) has led to unprecedented response and survival outcomes in patients with acute ...myeloid leukemia (AML). This has spurred the development of regimens combining venetoclax with other nucleoside analogs with distinct mechanisms of action. Here, we review older and newer nucleoside analogs, the rationale for their combination with venetoclax, and clinical evidence for the combination when available.
Venetoclax with HMA prolonged survival in a phase 3 study. Additionally, biologic correlates of response and resistance to venetoclax with HMA have been identified. The addition of venetoclax to standard intensive regimens containing higher doses of cytarabine and purine nucleoside analogs are safe and induce very high rates of remission and measurable residual disease negativity (MRD) negativity in newly diagnosed and relapsed/refractory AML. Investigational nucleoside analogs aim to improve upon the safety, bioavailability, or efficacy of approved venetoclax combinations and are currently being evaluated in clinical studies.
The development of venetoclax with HMA has transformed care for elderly adults with AML and opened the door for novel combinations of venetoclax with other nucleoside analogs. Further clinical studies are needed to see if these novel combinations further improve outcomes in AML particularly for patients with high-risk disease.
Minimal residual disease has emerged as an important prognostic factor for relapse and survival in acute myeloid leukemia. Eradication of minimal residual disease may increase the number of patients ...with long-term survival; however, to date, strategies that specifically target minimal residual disease are limited. Consensus guidelines on minimal residual disease detection by immunophenotypic and molecular methods are an essential initial step for clinical trials evaluating minimal residual disease. Here, we review promising targets of minimal residual disease prior to allogeneic stem cell transplantation. Specifically, the focus of this review is on the rationale and clinical development of therapies targeting: oncogenic driver mutations, apoptosis, methylation, and leukemic immune targets. We review the progress made in the clinical development of therapies against each target and the challenges that lie ahead.
Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome
. AML originates from a dominant mutation, then acquires collaborative ...transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient's leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60-92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background:
Ulnar collateral ligament injury and its subsequent surgical reconstruction are some of the most common issues among Major League Baseball (MLB) players.
Purpose/Hypothesis:
The purpose ...of this study was to determine factors predictive of ulnar collateral ligament reconstruction (UCLR) among MLB pitchers. The hypothesis was that pitchers who underwent UCLR would have higher preinjury peak fastball pitch velocity.
Study Design:
Case-control study; Level of evidence, 3.
Methods:
Data on pitch velocity, number, and type (fastball, curveball, etc) for every pitcher and game within MLB from April 2, 2007 to April 14, 2015 were gathered from the publically available PitchFx database. Pitcher demographic information was also recorded. Data from after 2012 were excluded to avoid lead-time bias. Using publically available information, the names and approximate dates of surgery for every MLB pitcher who ever underwent UCLR, including those before 2007 and after 2012, were collected. Each pitcher-game was then classified as “control,” “preinjury,” or “postoperative.” Control and preinjury pitchers were then compared to determine risk factors for UCLR.
Results:
Overall, 1327 pitchers were included, of whom 309 (26.8%) had undergone UCLR. Of these, 145 had preinjury velocity data. Peak pitch velocity was significantly higher among preinjury pitchers than control pitchers (mean 95% CI, 93.3 mph 92.8-93.8 vs 92.1 mph 91.9-92.3; P < .001), as was mean pitch velocity (87.8 mph 87.3-88.3 vs 86.9 mph 86.7-87.1; P = .001). Both demonstrated a dose-response relationship. Although height did not differ (P = .934), weight was significantly higher for preinjury pitchers than controls (P = .005). Pitch counts per year were significantly lower for preinjury pitchers compared with control pitchers, although preinjury pitchers threw more breaking pitches (P = .003). On multivariate regression, peak pitch velocity was the primary independent predictor of whether a pitcher underwent UCLR (P < .001), with mean velocity (P = .013), body mass index (P = .010), and age (P = .006) being secondary predictors. However, a model constructed with these variables only explained 7% of the variance in UCLR rates. Pitch counts were not significant predictors.
Conclusion:
Higher pitch velocity is the most predictive factor of UCLR in MLB pitchers, with higher weight and younger age being secondary predictors, although these factors only explained 7% of the variance in UCLR rates.
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FSPLJ, NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Abstract
In this paper, we situate our computational approach to philosophy relative to other digital humanities and computational social science practices, based on reflections stemming from our ...research on the PolyGraphs project in social epistemology. We begin by describing PolyGraphs. An interdisciplinary project funded by the Academies (BA, RS, and RAEng) and the Leverhulme Trust, it uses philosophical simulations (Mayo-Wilson and Zollman, 2021) to study how ignorance prevails in networks of inquiring rational agents. We deploy models developed in economics (Bala and Goyal, 1998), and refined in philosophy (O’Connor and Weatherall, 2018; Zollman, 2007), to simulate communities of agents engaged in inquiry, who generate evidence relevant to the topic of their investigation and share it with their neighbors, updating their beliefs on the evidence available to them. We report some novel results surrounding the prevalence of ignorance in such networks. In the second part of the paper, we compare our own to other related academic practices. We begin by noting that, in digital humanities projects of certain types, the computational component does not appear to directly support the humanities research itself; rather, the digital and the humanities are simply grafted together, not fully intertwined and integrated. PolyGraphs is notably different: the computational work directly supports the investigation of the primary research questions, which themselves belong decidedly within the humanities in general, and philosophy in particular. This suggests an affinity with certain projects in the computational social sciences. But despite these real similarities, there are differences once again: the computational philosophy we practice aims not so much at description and prediction as at answering the normative and interpretive questions that are distinctive of humanities research.
•Treatment-naive and relapsed/refractory MDS patients receiving venetoclax and HMAs have an ORR of 59% with 63% of responders proceeding to transplant.•Allogeneic stem cell transplantation after ...treatment with venetoclax in combination with HMA is associated with prolonged survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Clarke and Beck propose that the approximate number system (ANS) represents rational numbers. The evidence cited supports only the view that it represents ratios (and positive integers). Rational ...numbers are extensive magnitudes (i.e., sizes), whereas ratios are intensities. It is also argued that WHAT a system represents and HOW it does so are not as independent of one another as the authors assume.
Small molecule inhibitors targeting mutant FLT3, IDH1, and IDH2 as well as venetoclax-based combination therapies have expanded treatment options for patients with acute myeloid leukemia (AML). As ...the landmark trials leading to the approval of FLT3, IDH1, and IDH2 inhibitors in R/R-AML were conducted prior to the widespread use of venetoclax, it is unclear how these results apply in the current era of venetoclax based therapy frequently being used in the frontline treatment of AML.
In this multicenter, retrospective cohort study, we included 53 patients who received FLT3, IDH1 or IDH2 inhibitors after disease progression on venetoclax-based therapy. Among patients treated with targeted agents after venetoclax, the overall response rate (ORR; composite of complete remission CR/CR with incomplete count recovery, partial remission, and morphologic leukemia free state) was 17.7 % (n = 9 patients) and median OS of 4.2 months. Eight of 9 patients responding to targeted agents after venetoclax received gilteritinib. None of the patients with RAS pathway mutations responded to targeted agents after venetoclax. Additionally, mutations in TP53 and KRAS were associated with shorter OS among patients treated targeted agents.
Our data suggest that response rates to targeted therapies after venetoclax are low and novel therapeutic strategies are warranted.
•FLT3, IDH1, and IDH2 inhibitors after venetoclax have modest activity (ORR: 17 %).•Gilteritinib retained efficacy with ORR of 30 %.•No patient with RAS pathway mutations responded to targeted agents after venetoclax.•Median OS from the time of initiation of FLT3 or IDH1/2 inhibitors was 4.2 months.•Mutations in TP53 and KRAS were associated with shorter OS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological ...inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as AKT1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either PIM kinase or PI3K inhibitors. Both combinations decreased proliferation and induced apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Full integration of building energy modelling into the design and retrofit process has long been a goal of building scientists and practitioners. However, significant barriers still exist. Among them ...are the lack of available: (1) configurable technology stacks for performing both small- and large-scale analyses, (2) different classes of algorithms compatible with common design workflows, and (3) analysis tools for effectively visualizing large-scale simulation results. This article discusses the OpenStudio® Analysis Framework: a scalable analysis framework for building energy modelling that was developed to overcome the three barriers listed above. The framework is open-source and scalable to facilitate wider adoption and has a clearly defined application programming interface upon which other applications can be built. It runs on high-performance computing systems, within cloud infrastructure, and on laptops, and uses a common workflow to enable different classes of algorithms. Lessons learned from previous development efforts are also discussed.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
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