Real-World Use of Ruxolitinib in Patients with Myelofibrosis and Anemia or Thrombocytopenia at Diagnosis.

Introduction: Ruxolitinib is approved for treatment of myelofibrosis. We evaluated ruxolitinib in patients with anemia (hemoglobin <10 g/dL) or thrombocytopenia (platelet count ≤100 × 109/L) at diagnosis.

Methods: This was a retrospective, secondary analysis of a Cardinal Health Oncology Provider Extended Network medical chart review of adults with myelofibrosis diagnosed between 2012 and 2016 who received first-line ruxolitinib.

Direct and indirect costs for patients with myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are associated with substantial healthcare resource use and productivity loss. This retrospective cohort analysis used disability leave and medical claims data to measure direct and indirect healthcare costs associated with MPNs. The analysis included 173 patients with myelofibrosis (MF), 4477 with polycythemia vera (PV), 6061 with essential thrombocythemia (ET), and matched controls ( = 519,  = 13,431, and  = 18,183, respectively).

Silent cerebral infarction during immune TTP remission: prevalence, predictors, and impact on cognition.

Immune thrombotic thrombocytopenic purpura (iTTP) survivors have increased risk of cardiovascular disease, including strokes, and report persistent cognitive difficulties during remission. We conducted this prospective study involving iTTP survivors during clinical remission to determine the prevalence of silent cerebral infarction (SCI), defined as magnetic resonance imaging (MRI) evidence of brain infarction without corresponding overt neurodeficits. We also tested the hypothesis that SCI is associated with cognitive impairment, assessed using the National Institutes of Health ToolBox Cognition Battery.

Characterization of myeloproliferative neoplasms in the paediatric and young adult population.

The aim of this study was to compare the genomic features and clinical outcomes between paediatric and young adult patients (PAYA, <40 years) and older adults (OA, ≥40 years) with myeloproliferative neoplasms (MPN) to gain insight into pathogenesis, disease prognosis and management. Of 630 MPN patients, 171 (27%) were PAYA with an average age at diagnosis of 31 years. Females were more prevalent in PAYA than OA (71% vs 58%; p = 0.

Recurrent germline variant in ATM associated with familial myeloproliferative neoplasms.

Genetic predisposition (familial risk) in the myeloproliferative neoplasms (MPNs) is more common than the risk observed in most other cancers, including breast, prostate, and colon. Up to 10% of MPNs are considered to be familial. Recent genome-wide association studies have identified genomic loci associated with an MPN diagnosis.

The roles of sex and genetics in the MPN.

The Philadelphia chromosome negative myeloproliferative neoplasms(MPNs), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are acquired hematopoietic stem cell disorders driven by activating mutations of intracellular signal transduction pathways that control the production of circulating blood cells. The MPN are characterized clinically by marked variation in degrees of vascular risk, familial clustering, and evolution to myelofibrosis and acute leukemia. MPN disease presentations and outcomes are highly variable, and are markedly influenced by both sex and germline genetic variation.

Major adverse cardiovascular events in survivors of immune-mediated thrombotic thrombocytopenic purpura.

Cardiovascular disease is a leading cause of death in survivors of immune-mediated thrombotic thrombocytopenic purpura (iTTP), but the epidemiology of major adverse cardiovascular events (MACE) in iTTP survivors is unknown. We evaluated the prevalence and risk factors for MACE, defined as the composite of non-fatal or fatal myocardial infarction (MI), stroke, and cardiac revascularization, during clinical remission in two large iTTP cohorts (Johns Hopkins University and Ohio State University). Of 181 patients followed for ≥ 3 months after recovery from acute iTTP, 28.

Complement dysregulation is associated with severe COVID-19 illness.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may manifest as thrombosis, stroke, renal failure, myocardial infarction, and thrombocytopenia, reminiscent of other complement- mediated diseases. Multiple clinical and preclinical studies have implicated complement in the pathogenesis of COVID-19 illness. We previously found that the SARS-CoV-2 spike protein activates the alternative pathway of complement (APC) in vitro through interfering with the function of complement factor H, a key negative regulator of APC.

Germline / Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms.

Familial cases of myeloproliferative neoplasms (MPN) are relatively common, yet few inherited risk factors have been identified. Exome sequencing of a kindred with a familial cancer syndrome characterized by both MPN and melanoma produced a germline variant in the gene that co-segregates with disease. To further investigate whether germline variants contribute to MPN predisposition, the frequency of variants was analyzed in 1604 cases that underwent evaluation for hematologic malignancy, including 236 cases of MPN.

Outcomes of a clinician-directed protocol for discontinuation of complement inhibition therapy in atypical hemolytic uremic syndrome.

Terminal complement inhibition is the standard of care for atypical hemolytic uremic syndrome (aHUS). The optimal duration of complement inhibition is unknown, although indefinite therapy is common. Here, we present the outcomes of a physician-directed eculizumab discontinuation and monitoring protocol in a prospective cohort of 31 patients that started eculizumab for acute aHUS (and without a history of renal transplant).

Reduced sensitivity of PLASMIC and French scores for the diagnosis of thrombotic thrombocytopenic purpura in older individuals.

Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolysis, and ischemic organ failure. The PLASMIC and French TTP scores can help guide clinical decisions when ADAMTS13 testing is not immediately available. Older individuals often present atypically, but the impact of age on these tools is not known.

Ex vivo assays to detect complement activation in complementopathies.

In complement-driven thrombotic microangiopathies, failure to regulate complement activation leads to end-organ damage. The modified Ham (mHam) test measures complement-mediated killing of a nucleated cell in vitro but lacks a confirmatory assay and reliable positive controls. We demonstrate that C5b-9 accumulation on the surface of TF1 PIGAnull cells correlates with cell killing in the mHam.

Antiphospholipid syndrome: Complement activation, complement gene mutations, and therapeutic implications.

Antiphospholipid syndrome (APS) is an acquired thromboinflammatory disorder characterized by the presence of antiphospholipid antibodies as well as an increased frequency of venous or arterial thrombosis and/or obstetrical morbidity. The spectrum of disease varies from asymptomatic to a severe form characterized by widespread thrombosis and multiorgan failure, termed catastrophic APS (CAPS). CAPS affects only about ∼1% of APS patients, often presents as a thrombotic microangiopathy and has a fulminant course with >40% mortality, despite the best available therapy.

Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC).

Real-World Outcomes of Ruxolitinib Treatment for Polycythemia Vera.

Introduction: Ruxolitinib is approved for the treatment of polycythemia vera (PV) with hydroxyurea resistance or intolerance. Approval was based on the phase III RESPONSE trial, which demonstrated efficacy in a highly selected patient population.

Materials And Methods: To characterize the tolerability and outcomes of ruxolitinib outside of a clinical trial, we performed a multi-center retrospective analysis of patients with PV treated with ruxolitinib at 11 participating sites across the United States.

Sex determines the presentation and outcomes in MPN and is related to sex-specific differences in the mutational burden.

The factors underlying the variable presentation and clinical course of myeloproliferative neoplasms (MPNs) remain unclear. The aim of this study was to evaluate the independent effect of sex on MPN presentation and outcomes. A total of 815 patients with essential thrombocytosis, polycythemia vera, or primary myelofibrosis were evaluated between 2005 and 2019, and the association of sex with presenting phenotype, JAK2 V617F burden, progression, and survival was examined.

A review of the alternative pathway of complement and its relation to HELLP syndrome: is it time to consider HELLP syndrome a disease of the alternative pathway.

Complement is a part of the innate immune system with a critical role in host defense. Although essential for survival, when dysregulated or excessively triggered complement activation can cause tissue damage and drive inflammatory and immune disorders. The alternative pathway of complement (APC) is especially important for survival against infection and can be triggered by a variety of settings: infection, trauma, surgery, or pregnancy.