Drafting a blueprint for designing successful clinical trials in clonal haematopoiesis.

'As our understanding of the biology of clonal hematopoiesis expands, a pressing need in the field becomes the design and implementation of clinical trials to help mitigate the risk for progression to overt myeloid neoplasm. Effective clinical trial design will be informed by use of personalized genetic risk to determine eligibility, strategic endpoint selection, and identification of suitable interventions with a goldilocks balance of toxicity and reduced risk of progression. We will only reach this milestone through collaboration'.

Risk of bleeding in patients with essential thrombocythemia and extreme thrombocytosis.

Approximately 25% of patients with essential thrombocythemia (ET) present with extreme thrombocytosis (ExT), defined as having a platelet count ≥1000 × 109/L. ExT patients may have an increased bleeding risk associated with acquired von Willebrand syndrome. We retrospectively analyzed the risk of bleeding and thrombosis in ExT vs non-ExT patients with ET at Dana-Farber Cancer Institute and Massachusetts General Hospital from 2014 to 2022 to inform treatment decisions.

Effects of donor-engrafted clonal hematopoiesis in allogeneic and autologous stem cell transplantation: a systematic review and meta-analysis.

Donor stem cell health may be critically important to the success of hematopoietic stem cell transplantation (HSCT). Herein, we performed this systematic review and meta-analysis including meta-regression to assess the impact of donor-engrafted clonal hematopoiesis (CH) in allogeneic HSCT (allo-HSCT) and impact of pre-transplant CH in autologous HSCT (auto-HSCT). We applied random-effects models to analyze 5 allo-HSCT studies with 3192 donor-recipient pairs and 9 auto-HSCT studies with 2854 patients.

Clonal Hematopoiesis Risk Score and All-Cause and Cardiovascular Mortality in Older Adults.

Importance: Clonal hematopoiesis (CH) with acquired pathogenic variants in myeloid leukemia driver genes is common in older adults but of unknown prognostic value.

Objective: To investigate the prevalence of CH and the utility of the CH risk score (CHRS) in estimating all-cause and disease-specific mortality in older adults with CH.

Design, Setting, And Participants: This population-based prospective cohort study involved community-dwelling older adults (aged 67-90 years) without hematologic malignant neoplasms (HMs) who were participants in the Atherosclerosis Risk in Communities Visit 5 at 4 US centers: Forsyth County, North Carolina; Jackson, Mississippi; Minneapolis, Minnesota; and Washington County, Maryland.

Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias.

Background And Aims: Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias.

Methods: UK Biobank participants without prevalent arrhythmias were included.

Causes and consequences of clonal hematopoiesis.

Clonal hematopoiesis (CH) is described as the outsized contribution of expanded clones of hematopoietic stem and progenitor cells (HSPCs) to blood cell production. The prevalence of CH increases dramatically with age. CH can be caused by somatic mutations in individual genes or by gains and/or losses of larger chromosomal segments.

Association of Somatic TET2 Mutations With Giant Cell Arteritis.

Objective: Giant cell arteritis (GCA) is an age-related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HMs). How the presence of somatic mutations that drive the development of HMs, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood.

Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease.

Background: Clonal hematopoiesis of indeterminate potential (CHIP)-the age-related clonal expansion of blood stem cells with leukemia-associated mutations-is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear.

Objectives: This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD.

Nelarabine combination therapy for relapsed or refractory T-cell acute lymphoblastic lymphoma/leukemia.

Nelarabine, an antimetabolite prodrug, is approved as monotherapy for children and adults with relapsed and refractory T-cell acute lymphoblastic leukemia and lymphoma (R/R T-ALL/LBL), although it is often used in combination regimens. We sought to understand differences in efficacy and toxicity when nelarabine is administered alone or in combination. We retrospectively analyzed 44 consecutive patients with R/R T-ALL/LBL; 29 of whom were treated with combination therapy, most with cyclophosphamide and etoposide (23, 79%) and 15 with monotherapy.

TET2-mutant clonal hematopoiesis and risk of gout.

Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease.

Burnout in US hematologists and oncologists: impact of compensation models and advanced practice provider support.

Burnout is prevalent throughout medicine. Few large-scale studies have examined the impact of physician compensation or clinical support staff on burnout among hematologists and oncologists. In 2019, the American Society of Hematology conducted a practice survey of hematologists and oncologists in the AMA (American Medical Association) Masterfile; burnout was measured using a validated, single-item burnout instrument from the Physician Work-Life Study, while satisfaction was assessed in several domains using a 5-point Likert scale.

Impact of COVID-19 on Hematology-Oncology Fellowship Programs: A Quantitative and Qualitative Survey Assessment of Fellowship Program Directors.

Purpose: The COVID-19 pandemic led to unprecedented challenges in medical training, and we sought to assess the specific impact of COVID-19 on hematology-oncology (HO) fellowship programs.

Methods: We conducted a cross-sectional anonymous online survey of 103 HO program directors (PDs) in conjunction with the American Society of Hematology (ASH) and ASCO. We sought to assess the specific impact of COVID-19 on HO fellowship programs' clinical, educational, and research activities, evaluate perceptions regarding PD and trainee emotional and mental health, and identify ways to support programs.

Impact of COVID-19 on Hematology-Oncology Trainees: A Quantitative and Qualitative Assessment.

Purpose: Graduate medical and research training has drastically changed during the COVID-19 pandemic, with widespread implementation of virtual learning, redeployment from core rotations to the care of patients with COVID-19, and significant emotional and physical stressors. The specific experience of hematology-oncology (HO) fellows during the COVID-19 pandemic is not known.

Methods: We conducted a mixed-methods study using a survey of Likert-style and open-ended questions to assess the training experience and well-being of HO fellows, including both clinical and postdoctoral trainee members of the American Society of Hematology and ASCO.

Management of therapeutic unfractionated heparin in COVID-19 patients: A retrospective cohort study.

Background: Patients hospitalized with severe acute respiratory syndrome coronavirus 2 infection are at risk for thrombotic complications necessitating use of therapeutic unfractionated heparin (UFH). Full-dose anticoagulation limits requirements for organ support interventions in moderately ill patients with coronavirus disease 2019 (COVID-19). Given this benefit, it is important to evaluate response to therapeutic anticoagulation in this population.

Bridging the Divide: Student Grand Rounds at the Interface of Basic Science and Clinical Medicine.

Problem: As biomedical research and clinical medicine become increasingly complex, physician-scientists and clinically oriented biomedical researchers play important roles in bridging the gap between disciplines. A lack of educational programming that addresses the unique needs of students preparing for careers at the interface of basic science and clinical medicine may contribute to trainee attrition.

Approach: The MD-PhD/LHB Grand Rounds was introduced in 2008 as a trainee-driven collaborative effort of the Harvard/Massachusetts Institute of Technology MD-PhD program at Harvard Medical School (HMS MD-PhD program), Harvard's Leder Human Biology and Translational Medicine (LHB) program, and the Brigham and Women's Hospital (BWH) Internal Medicine Department.

Identification of Racial Inequities in Access to Specialized Inpatient Heart Failure Care at an Academic Medical Center.

Background: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race.

Monoclonal gammopathy of undetermined significance.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell dyscrasia that consistently precedes multiple myeloma (MM) with a 1% risk of progression per year. Recent advances have improved understanding of the complex genetic and immunologic factors that permit progression from the aberrant plasma cell clone to MGUS and overt MM. Additional evidence supports bidirectional interaction of MGUS cells with surrounding cells in the bone marrow niche that regulates malignant transformation.

Radiosensitization of non-small-cell lung cancer cells and xenografts by the interactive effects of pemetrexed and methoxyamine.

Background And Purpose: The anti-folate pemetrexed is a radiosensitizer. In pre-clinical models, pemetrexed is more effective along with the base-excision-repair inhibitor methoxyamine. We tested whether methoxyamine enhances pemetrexed-mediated radiosensitization of lung adenocarcinoma cells and xenografts.

Uracil-DNA glycosylase expression determines human lung cancer cell sensitivity to pemetrexed.

Uracil misincorporation into DNA is a consequence of pemetrexed inhibition of thymidylate synthase. The base excision repair (BER) enzyme uracil-DNA glycosylase (UNG) is the major glycosylase responsible for removal of misincorporated uracil. We previously illustrated hypersensitivity to pemetrexed in UNG(-/-) human colon cancer cells.