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Seminars in Hematology

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https://www.readbyqxmd.com/read/30032754/expanding-complement-therapeutics-for-the-treatment-of-paroxysmal-nocturnal-hemoglobinuria
#1
REVIEW
Dimitrios C Mastellos, Edimara S Reis, Despina Yancopoulou, Antonio M Risitano, John D Lambris
Paroxysmal nocturnal hemoglobinuria (PNH) is widely regarded as an archetypal complement-mediated disorder that has propelled complement drug discovery in recent decades. Its pathology is driven by chronic complement dysregulation resulting from the lack of the glycosyl phosphatidyl inositol-linked regulators DAF and CD59 on susceptible erythrocytes. This complement imbalance fuels persistent C3 activation on affected erythrocytes, which culminates in chronic complement-mediated intravascular hemolysis. The clinical application of eculizumab, a humanized anti-C5 antibody that blocks terminal pathway activation, has led to drastic improvement of therapeutic outcomes but has also unveiled hitherto elusive pathogenic mechanisms that are now known to contribute to the clinical burden of a significant proportion of patients with PNH...
July 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/30032753/complement-in-pathophysiology-and-treatment-of-transplant-associated-thrombotic-microangiopathies
#2
REVIEW
Sonata Jodele
Transplant-associated thrombotic microangiopathy (TA-TMA) is a form of microangiopathy specifically occurring in the context of hematopoietic stem cell transplantation. Similarly, to other microangiopathies, TA-TMA is characterized by hemolytic anemia, thrombocytopenia, and organ failure due to endothelial injury. Although its clinical association with medications (eg, calcineurin inhibitors), immune reactions (eg, graft vs host disease) or infectious complications is well established, the pathophysiology remains largely unknown...
July 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/30032752/anticomplement-treatment-in-atypical-and-typical-hemolytic-uremic-syndrome
#3
REVIEW
Fadi Fakhouri, Chantal Loirat
The dissection of the pathogenic mechanisms of the various forms of the hemolytic uremic syndrome (HUS) has paved the way for the design of specific efficacious treatments. Such mechanistic approach led to a revolution in the management of atypical HUS with the use of the first-in class C5 blocker, eculizumab. The availability of this anticomplement drug has also raised unsettled questions regarding the cost or burden and optimal duration of therapy and its use in secondary HUS. The efficacy of eculizumab in Shiga toxin producing Escherichia coli-associated HUS is not to date established and the results of ongoing prospective studies are eagerly awaited...
July 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/30032751/complement-activation-and-inhibition-in-autoimmune-hemolytic-anemia-focus-on-cold-agglutinin-disease
#4
REVIEW
Sigbjørn Berentsen
The classical complement pathway and, to some extent, the terminal pathway, are involved in the immune pathogenesis of autoimmune hemolytic anemia (AIHA). In primary cold agglutinin disease (CAD), secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria, the hemolytic process is entirely complement dependent. Complement activation also plays an important pathogenetic role in some warm-antibody AIHAs, especially when immunoglobulin M is involved. This review describes the complement-mediated hemolysis in AIHA with a major focus on CAD, in which activation of the classical pathway is essential and particularly relevant for complement-directed therapy...
July 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/30032750/congenital-defects-in-the-expression-of-the-glycosylphosphatidylinositol-anchored-complement-regulatory-proteins-cd59-and-decay-accelerating-factor
#5
REVIEW
Taroh Kinoshita
CD59 and decay-accelerating factor (DAF) are glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins critical for regulating complement activation on the host cell surface. Defective expressions of CD59 or DAF caused by mutations in the genes coding for these proteins or genes involved in the biosynthesis of GPI, such as PIGA, PIT, and PIGM, are associated with various clinical symptoms that are mediated by dysregulated activation of complement, especially the C5 component. Eculizumab, an anti-C5 antibody, is effective in relieving the symptoms seen in patients with complement dysregulation...
July 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/30032749/c3-mediated-extravascular-hemolysis-in-pnh-on-eculizumab-mechanism-and-clinical-implications
#6
REVIEW
Rosario Notaro, Michela Sica
The introduction of eculizumab, a human monoclonal antibody against the C5 component of complement, has changed radically the management of paroxysmal nocturnal hemoglobinuria (PNH). The blockade of the terminal complement pathway by eculizumab abrogates intravascular hemolysis, reduces the transfusion requirement and the risk of thrombosis in most of hemolytic PNH patients. However, in almost all PNH patients on eculizumab arises a fraction of PNH red cells that bind fragments of C3 and become a potential target of phagocytosis by macrophages...
July 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/30032748/ten-years-of-clinical-experience-with-eculizumab-in-patients-with-paroxysmal-nocturnal-hemoglobinuria
#7
REVIEW
Flore Sicre de Fontbrune, Régis Peffault de Latour
Paroxysmal nocturnal hemoglobinuria (PNH) arises from a somatic mutation in the phosphatidylinositol glycan class A, X-linked gene, responsible for a deficiency in glycosyl phosphatidylinositol-anchored proteins. The absence of one of the glycosyl phosphatidylinositol-anchored protein complement regulatory proteins (CD59) leads to hemolysis. Clinical manifestations include chronic hemolysis, thromboembolic disease, infectious complications, chronic kidney injury, pulmonary hypertension, and smooth muscle dysfunction...
July 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/30032747/mechanisms-of-complement-mediated-damage-in-hematological-disorders
#8
REVIEW
Ronald P Taylor, Margaret A Lindorfer
The complement cascade is an ancient defense system that destroys and eliminates threats to normal homeostasis in the bloodstream and tissues. Although multiple controls keep complement in check to minimize innocent bystander injury to normal cells and tissues, defects in complement regulation due to mutations in, or autoantibodies to, complement control proteins underlie the pathogenesis of several hemolytic diseases including paroxysmal nocturnal hemoglobinuria, and atypical hemolytic uremic syndrome. In autoimmune hemolytic anemias complement plays an important role in erythrocyte destruction mediated by antierythrocyte antibodies...
July 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/30032746/therapeutic-complement-modulation-for-hematological-diseases-where-we-stand-and-where-we-are-going
#9
EDITORIAL
Antonio M Risitano
No abstract text is available yet for this article.
July 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/29958565/when-there-is-no-match-the-game-is-not-over-alternative-donor-options-for-hematopoietic-stem-cell-transplantation-in-sickle-cell-disease
#10
REVIEW
Jacinth J Joseph, Allistair A Abraham, Courtney D Fitzhugh
Many patients with sickle cell disease experience severe morbidity and early mortality. The only curative option remains hematopoietic stem cell transplantation. Although HLA-matched sibling transplantation has been very successful for adults and children, the vast majority of patients with sickle cell disease do not have an HLA-matched sibling. Alternative donor options include haploidentical, unrelated umbilical cord blood, and matched unrelated donor transplantation. This report summarizes major alternative donor transplantation studies reported to date and ongoing and upcoming clinical trials...
April 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/29958564/curative-therapies-allogeneic-hematopoietic-cell-transplantation-from-matched-related-donors-using-myeloablative-reduced-intensity-and-nonmyeloablative-conditioning-in-sickle-cell-disease
#11
REVIEW
Gregory M T Guilcher, Tony H Truong, Santosh L Saraf, Jacinth J Joseph, Damiano Rondelli, Matthew M Hsieh
Sickle cell disease (SCD) chronically damages multiple organs over the lifetime of affected individuals. Allogeneic hematopoietic cell transplantation (allo-HCT) is the most studied curative intervention. Fully matched related marrow, peripheral blood derived, or cord blood HCT have the best transplant outcome for symptomatic patients with SCD. For patients with asymptomatic or milder disease who have this donor option available, risks and benefits of HCT should be discussed among the patient, family, treating hematologist, and transplant physician, and decision to proceed to HCT should be individualized...
April 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/29958563/genetic-therapies-for-sickle-cell-disease
#12
REVIEW
Erica B Esrick, Daniel E Bauer
After decades with few novel therapeutic options for sickle cell disease (SCD), autologous hematopoietic stem cell (HSC) based genetic therapies including lentiviral gene therapy (GT), and genome editing (GE) now appear imminent. Lentiviral GT has advanced considerably in the past decade with promising clinical trial results in multiple disorders. For β-hemoglobinopathies, GT strategies of gene addition and fetal hemoglobin induction through BCL11A regulation are both being evaluated in open clinical trials...
April 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/29958562/fetal-hemoglobin-induction-by-epigenetic-drugs
#13
REVIEW
Donald Lavelle, James Douglas Engel, Yogen Saunthararajah
Fetal hemoglobin (HbF) inhibits the root cause of sickle pathophysiology, sickle hemoglobin polymerization. Individuals who naturally express high levels of HbF beyond infancy thus receive some protection from sickle complications. To mimic this natural genetic experiment using drugs, one guiding observation was that HbF is increased during recovery of bone marrow from extreme stress. This led to evaluation and approval of the cytotoxic (cell killing) drug hydroxyurea to treat sickle cell disease. Cytotoxic approaches are limited in potency and sustainability, however, since they require hematopoietic reserves sufficient to repeatedly mount recoveries from stress that destroys their counterparts, and such reserves are finite...
April 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/29958561/sickle-cell-disease-unanswered-questions-and-future-directions-in-therapy
#14
EDITORIAL
Swee Lay Thein, John Tisdale
No abstract text is available yet for this article.
April 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/29759154/mrd-testing-in-multiple-myeloma-the-main-future-driver-for-modern-tailored-treatment
#15
REVIEW
Ola Landgren, Sydney X Lu, Malin Hultcrantz
The past decade, several highly efficacious drugs have been approved for the treatment of multiple myeloma. Many of these newer drugs are less toxic than older chemotherapy drugs. Using modern combination therapy in newly diagnosed multiple myeloma patients, high proportions of newly diagnosed multiple myeloma patients obtain minimal residual disease (MRD) negativity and MRD testing has rapidly become an integral part of clinical trials focusing on patients in this setting. Only recently, MRD negativity was reported in clinical trials focusing on older newly diagnosed multiple myeloma patients (ie, nontransplant candidates), as well as studies focusing on patients with relapsed or refractory multiple myeloma...
January 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/29759153/mass-spectrometry-methods-for-detecting-monoclonal-immunoglobulins-in-multiple-myeloma-minimal-residual-disease
#16
REVIEW
Katie L Thoren
Mass spectrometry methods that can detect low levels of monoclonal immunoglobulin in serum have recently been developed. These assays are based on the principle that each immunoglobulin has a unique amino acid sequence and therefore, has a unique mass. This mass can be used as a surrogate marker in order to monitor a patient's disease over time and at low levels. Here, we explain these methods, discuss their advantages and disadvantages and how they may be used to monitor monoclonal immunoglobulins for minimal residual disease detection in multiple myeloma...
January 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/29759152/minimal-residual-disease-detection-by-flow-cytometry-in-multiple-myeloma-why-and-how
#17
REVIEW
Mikhail Roshal
The outlook for myeloma patients has steadily improved with the introduction of newer drug combinations in recent years. Unlike older therapies that largely achieved only modest levels of neoplastic clone reduction, the newer drug combinations have led to deeper suppression of myeloma clones in most patients. Frequently the neoplastic clones become undetectable with traditional disease evaluation approaches. Recent studies using ultrasensitive disease monitoring have demonstrated that patients with disease undetectable by traditional techniques show wide heterogeneity in disease levels varying by several orders of magnitude...
January 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/29759151/circulating-tumour-dna-for-detecting-minimal-residual-disease-in-multiple-myeloma
#18
REVIEW
Trevor J Pugh
Circulating tumor DNA faithfully recapitulates somatic mutations detected in bone marrow aspirates from patients with newly diagnosed or relapsed or recurrent myeloma. Extending these methods to enable detection of minimal residual disease will require increased sensitivity and breadth of genomic assays to maximize information content from small quantities of cell-free DNA; as well as definition of a clinically meaningful ctDNA concentration in comparison with conventional bone marrow cell-count thresholds...
January 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/29759150/comprehensive-characterization-of-circulating-and-bone-marrow-derived-multiple-myeloma-cells-at-minimal-residual-disease
#19
REVIEW
Johannes M Waldschmidt, Praveen Anand, Birgit Knoechel, Jens G Lohr
The presence or absence of minimal residual disease (MRD) in patients with multiple myeloma (MM) has emerged as a useful marker to determine the depth of remission. MRD negativity as an endpoint has been shown to be associated with improved progression-free survival in many studies. MRD detection is therefore part of numerous clinical trial protocols for MM. At the present time, two methodologies are most widely accepted for MRD detection: (1) multicolor flow cytometry and (2) next-generation sequencing-based clonotype detection...
January 2018: Seminars in Hematology
https://www.readbyqxmd.com/read/29759149/functional-imaging-methods-for-assessment-of-minimal-residual-disease-in-multiple-myeloma-current-status-and-novel-immunopet-based-methods
#20
REVIEW
Neeta Pandit-Taskar
Imaging plays a key role in assessment of myeloma. Osteolytic bone lesions are optimally assessed using structural imaging, however the structural changes lag the functional changes in the disease. Functional imaging with fluoro deoxy glucose (FDG) positron emission tomography (PET) computerized tomography (CT) is useful in assessment of high-risk myeloma. FDG PET provides prognostic information and is helpful in monitoring response to therapy. However, it is nonspecific and may not be optimal in assessing treatment response to immunotherapeutic agents...
January 2018: Seminars in Hematology
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