Avapritinib versus Placebo in Indolent Systemic Mastocytosis.

BACKGROUND: Indolent systemic mastocytosis (ISM) is a clonal mast-cell disease driven by the KIT D816V mutation. We assessed the efficacy and safety of avapritinib versus placebo, both with best supportive care, in patients with ISM. METHODS: We randomized patients with moderate to severe ISM (total symptom score [TSS] of ≥28; scores range from 0 to 110, with higher numbers indicating more severe symptoms) two to one to avapritinib 25 mg once daily (n=141) or placebo (n=71).

Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma.

Purpose: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy.

Experimental Design: We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients.

Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) and determination of a threshold score for moderate symptoms.

Background: The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) (©Blueprint Medicines Corporation), a 12-item daily diary that assesses 11 signs and symptoms of indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM), was psychometrically evaluated among patients with ISM. Additionally, thresholds of the ISM-SAF total symptom score (TSS) to distinguish patients with moderate to severe symptoms from those with mild symptoms were evaluated.

Methods: The ISM-SAF was completed daily as an electronic diary in a prospective, observational study utilizing an online survey of patients with ISM in the United States.

The Influence of Saliva and Blood Contamination on Bonding Between Resin-modified Glass Ionomer Cements and Resin Composite.

Objective: To investigate the influence of blood and saliva contamination on the microshear bond strength (μSBS) between resin-modified glass ionomer cement (RMGIC) and resin composite (RC).

Methods And Materials: Eighty RMGIC discs were allocated into four groups (n=20). Group 1 received universal dental adhesive application in a self-etch mode followed by a build-up with RC.

Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial.

Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study ( NCT02561988 ) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib.

Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial.

Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655 ) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62).

Psychometric evaluation of the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) in a phase 2 clinical study.

Background: Indolent systemic mastocytosis (ISM) is a rare, clonal mast cell neoplasm characterized by severe, unpredictable symptoms. The Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) items compose a Total Symptom Score (TSS), Gastrointestinal Symptom Score (GSS), and Skin Symptom Score (SSS) to assess symptom severity. This study evaluated the psychometric performance of ISM-SAF among ISM patients.

Development of symptom-focused outcome measures for advanced and indolent systemic mastocytosis: the AdvSM-SAF and ISM-SAF.

Background: Advanced systemic mastocytosis (AdvSM), indolent systemic mastocytosis (ISM), and smoldering systemic mastocytosis (SSM) are rare diseases characterized by neoplastic mast cell infiltration of more than one organ. A content-valid patient-reported outcome (PRO) questionnaire that assesses relevant signs and symptoms that are important and understandable to individuals with a condition is critical for assessing new treatment benefit as well as supporting product labeling claims. Notably, no such PRO questionnaire has been developed in accordance with regulatory and scientific guidelines for use in AdvSM, ISM, and SSM patient populations.

Psychometric evaluation of the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF).

Background: The Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) was developed to evaluate symptoms of advanced systemic mastocytosis (AdvSM). This study aimed to psychometrically evaluate AdvSM-SAF scores and provide score interpretation guidelines.

Methods: The 10-item AdvSM-SAF was administered daily (scored as a seven-day average) in EXPLORER, an open-label Phase 1 study in AdvSM.

-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells.

Truncating mutations in the terminal exon of protein phosphatase Mg2/Mn2 1D () have been identified in clonal hematopoiesis and myeloid neoplasms, with a striking enrichment in patients previously exposed to chemotherapy. In this study, we demonstrate that truncating mutations confer a chemoresistance phenotype, resulting in the selective expansion of -mutant hematopoietic cells in the presence of chemotherapy in vitro and in vivo. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease mutational profiling of in the presence of chemotherapy selected for the same exon 6 mutations identified in patient samples.

alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia.

Mutations in encoding the histone 3 lysine 36 trimethyltransferase, are enriched in relapsed acute lymphoblastic leukemia and MLL-rearranged acute leukemia. We investigated the impact of mutations on chemotherapy sensitivity in isogenic leukemia cell lines and in murine leukemia generated from a conditional knockout of mutations led to resistance to DNA-damaging agents, cytarabine, 6-thioguanine, doxorubicin, and etoposide, but not to a non-DNA damaging agent, l-asparaginase. H3K36me3 localizes components of the DNA damage response (DDR) pathway and mutation impaired DDR, blunting apoptosis induced by cytotoxic chemotherapy.

The relative utilities of genome-wide, gene panel, and individual gene sequencing in clinical practice.

Advances in technology that have transpired over the past 2 decades have enabled the analysis of cancer samples for genomic alterations to understand their biologic function and to translate that knowledge into clinical practice. With the power to analyze entire genomes in a clinically relevant time frame and with manageable costs comes the question of whether we ought to and when. This review focuses on the relative merits of 3 approaches to molecular diagnostics in hematologic malignancies: indication-specific single gene assays, gene panel assays that test for genes selected for their roles in cancer, and genome-wide assays that broadly analyze the tumor exomes or genomes.

Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with mutations.

Heterozygous inactivating mutations in ribosomal protein genes (RPGs) are associated with hematopoietic and developmental abnormalities, activation of p53, and altered risk of cancer in humans and model organisms. Here we performed a large-scale analysis of cancer genome data to examine the frequency and selective pressure of RPG lesions across human cancers. We found that hemizygous RPG deletions are common, occurring in about 43% of 10,744 cancer specimens and cell lines.

Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation.

Background: Genetic mutations drive the pathogenesis of the myelodysplastic syndrome (MDS) and are closely associated with clinical phenotype. Therefore, genetic mutations may predict clinical outcomes after allogeneic hematopoietic stem-cell transplantation.

Methods: We performed targeted mutational analysis on samples obtained before transplantation from 1514 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014.

Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma.

Purpose Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in the blood of otherwise healthy adults. We hypothesized that in patients undergoing autologous stem-cell transplantation (ASCT) for lymphoma, CHIP at the time of ASCT would be associated with an increased risk of myelodysplastic syndrome and acute myeloid leukemia, collectively termed therapy-related myeloid neoplasm (TMN), and other adverse outcomes. Methods We performed whole-exome sequencing on pre- and post-ASCT samples from 12 patients who developed TMN after autologous transplantation for Hodgkin lymphoma or non-Hodgkin lymphoma and targeted sequencing on cryopreserved aliquots of autologous stem-cell products from 401 patients who underwent ASCT for non-Hodgkin lymphoma between 2003 and 2010.

Depolymerization Pathways for Branching Lignin Spirodienone Units Revealed with ab Initio Steered Molecular Dynamics.

Lignocellulosic biomass is an abundant, rich source of aromatic compounds, but direct utilization of raw lignin has been hampered by both the high heterogeneity and variability of linking bonds in this biopolymer. Ab initio steered molecular dynamics (AISMD) has emerged both as a fruitful direct computational screening approach to identify products that occur through mechanical depolymerization (i.e.

The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease with complex molecular pathophysiology. To systematically characterize AML's genetic dependencies, we conducted genome-scale short hairpin RNA screens in 17 AML cell lines and analyzed dependencies relative to parallel screens in 199 cell lines of other cancer types. We identified 353 genes specifically required for AML cell proliferation.

Functionally identifiable apoptosis-insensitive subpopulations determine chemoresistance in acute myeloid leukemia.

Upfront resistance to chemotherapy and relapse following remission are critical problems in leukemia that are generally attributed to subpopulations of chemoresistant tumor cells. There are, however, limited means for prospectively identifying these subpopulations, which hinders an understanding of therapeutic resistance. BH3 profiling is a functional single-cell analysis using synthetic BCL-2 BH3 domain-like peptides that measures mitochondrial apoptotic sensitivity or "priming.

Adapting DFT+U for the Chemically Motivated Correction of Minimal Basis Set Incompleteness.

Recent algorithmic and hardware advances have enabled the application of electronic structure methods to the study of large-scale systems such as proteins with O(10(3)) atoms. Most such methods benefit greatly from the use of reduced basis sets to further enhance their speed, but truly minimal basis sets are well-known to suffer from incompleteness error that gives rise to incorrect descriptions of chemical bonding, preventing minimal basis set use in production calculations. We present a strategy for improving these well-known shortcomings in minimal basis sets by selectively tuning the energetics and bonding of nitrogen and oxygen atoms within proteins and small molecules to reproduce polarized double-ζ basis set geometries at minimal basis set cost.

Ab Initio Screening Approach for the Discovery of Lignin Polymer Breaking Pathways.

The directed depolymerization of lignin biopolymers is of utmost relevance for the valorization or commercialization of biomass fuels. We present a computational and theoretical screening approach to identify potential cleavage pathways and resulting fragments that are formed during depolymerization of lignin oligomers containing two to six monomers. We have developed a chemical discovery technique to identify the chemically relevant putative fragments in eight known polymeric linkage types of lignin.

Acute myeloid leukemia ontogeny is defined by distinct somatic mutations.

Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients.

Age-related clonal hematopoiesis associated with adverse outcomes.

Background: The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders.

A remote stereochemical lever arm effect in polymer mechanochemistry.

Molecular mechanisms by which to increase the activity of a mechanophore might provide access to new chemical reactions and enhanced stress-responsive behavior in mechanochemically active polymeric materials. Here, single-molecule force spectroscopy reveals that the force-induced acceleration of the electrocyclic ring opening of gem-dichlorocyclopropanes (gDCC) is sensitive to the stereochemistry of an α-alkene substituent on the gDCC. On the ∼0.