bluuebunny/crossref_metadata_2025_split huggingface dataset:
Roundtable: How I treat a newly diagnosed patient with high-risk myeloma
Authors: Kaufman Jonathan L. 
Published: December 2019

AbstractInitial management of high-risk myeloma remains a treatment challenge. Risk is defined by a combination of clinical and biological features, with fluorescence in situ hybridization detection of specific cytogenetic abnormalities driving categorization. High-risk abnormalities include t(4;14), t(14;16), t(14;20), del(17p), and +1q. Clinical features such as plasma cell leukemia, presence of 5% to 20% circulating plasma cells, and extramedullary disease all are factors in high-risk presentations. The driving principle of treatment of the high-risk patient is the use of a regimen with the greatest likelihood of a deep and prolonged remission, as defined by minimal residual disease negativity. I will describe prior and current treatment approaches, including induction, the role of autologous transplantation, and posttransplantation consolidation and maintenance therapy selection using the best available data to provide a rationale for these decisions. This case-based roundtable walks through treatment of a patient with newly diagnosed high-risk myeloma.
Idiopathic aplastic anemia vs hypocellular myelodysplastic syndrome
Authors: Durrani Jibran , Maciejewski Jaroslaw P. 
Published: December 2019

Abstract
Proper diagnostic distinction of bone marrow failure syndromes can often be challenging. In particular, for older patients with idiopathic aplastic anemia (AA), differential diagnosis includes myelodysplastic syndrome (MDS), which can atypically present in a hypocellular form. In addition to blasts and overt dysplasia, the presence of chromosomal abnormalities and a spectrum of somatic mutations may be revealing. Both clonal cytogenetic aberrations and somatic mutations most typically correspond to a clonal myelodysplasia, but clonal somatic mutations have also recently been found in AA. True driver myeloid mutations are uncommon in AA. Marrow hypocellularity in AA and occasionally in MDS patients points toward a similar immune mechanism responsible for deficient blood cell production and indicates that cytopenias in early hypocellular MDS might be treated with immunosuppressive modalities. Primary hypocellular MDS has to be distinguished from post-AA secondary MDS, most commonly associated with del7/7q. Post-AA MDS evolves at the rate of about 10% in 10 years, but recent observations suggest that widespread use of eltrombopag may influence the risk of progression to MDS. This complication likely represents a clonal escape, with founder hits occurring early on in the course of AA. A similar mechanism operates in the evolution of paroxysmal nocturnal hemoglobinuria (PNH) in AA patients, but PNH clones are rarely encountered in primary MDS.
Genetic predisposition to MDS: diagnosis and management
Authors: Furutani Elissa , Shimamura Akiko 
Published: December 2019

AbstractMyelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by clonal hematopoiesis with a propensity to evolve into acute myeloid leukemia. MDS presenting in children and young adults is associated with features clinically and biologically distinct from MDS arising in older adults. MDS presenting in children and young adults is associated with a higher likelihood of an underlying genetic predisposition; however, genetic predisposition is increasingly recognized in a subset of older adults. The diagnosis of a genetic predisposition to MDS informs clinical care and treatment selection. Early diagnosis allows a tailored approach to management and surveillance. Genetic testing now offers a powerful diagnostic approach but also poses new challenges and caveats. Clinical expertise in these disorders together with scientific expertise regarding the affected genes is essential for diagnosis. Understanding the basic mechanisms of genetic predisposition to myeloid malignancies may inform surveillance strategies and lead to novel therapies. The cases presented in this article illustrate challenges to the diagnosis of germline genetic predisposition to MDS and how the diagnosis affects clinical management and treatment.
Is there a role for low-dose DOACs as prophylaxis?
Authors: Cohen Alexander T. , Hunt Beverley J. 
Published: December 2019

Abstract
The direct oral anticoagulants (DOACs) have transformed the management of thrombotic disorders. Large clinical trials have demonstrated that DOACs can replace vitamin K antagonists (VKAs) in the 2 existing major indications for anticoagulation: the prevention of stroke in atrial fibrillation and the acute treatment and secondary prevention of venous thromboembolism (VTE); this literature is widely known. In this article, we will concentrate on the less well-discussed benefits of the use of DOACs—using low doses as primary and secondary prophylaxis in both venous and arterial thromboprophylaxis. The attractiveness of using a low-dose DOAC is that the bleeding risk seems to be slightly lower than with the standard dose and significantly lower than with VKAs so that they can be used safely for long periods, where previously, VKAs had risk/benefit ratios that did not permit this. We discuss in detail the extended use of low-dose DOACs in secondary VTE prevention. We also cover the utility of low-dose DOACs in the evolving fields of prevention of hospital-associated VTE in acutely ill medical patients, after total hip and knee replacement, and in cancer patients. To complete the indications, we briefly discuss the role of low-dose DOACs in the secondary prevention of arterial vascular events.
Direct oral anticoagulant monitoring: what laboratory tests are available to guide us?
Authors: Sarode Ravi 
Published: December 2019

Abstract
Direct oral anticoagulants (DOACs) are increasingly used in the treatment and prophylaxis of thromboembolism because of several advantages over vitamin K antagonists, including no need for laboratory monitoring. However, it has become increasingly important in certain clinical scenarios to know either actual DOAC concentration (quantitative) or presence of DOAC (qualitative). These clinical conditions include patients presenting with major bleeding or requiring urgent surgery who may need a reversal or hemostatic agent, extremes of body weight, failed therapy, etc. Prothrombin time and activated partial thromboplastin time are variably affected by factor Xa inhibitors (FXaIs) and direct thrombin inhibitor (DTI), respectively, depending on reagents’ sensitivity, and hence, they cannot be relied on confidently. Thrombin time is highly sensitive to very low amounts of DTI; thus, normal value rules out a clinically significant amount. Liquid chromatography mass spectrometry accurately measures DOAC levels but is clinically impractical. Dilute thrombin time and ecarin-based assays using appropriate calibrators/controls provide an accurate DTI level. Anti-Xa assay using corresponding FXaI calibrators/controls provides accurate drug levels. However, these assays are not readily available in the United States compared with some other parts of the world. Heparin assays using anti-Xa activity often have a linear relationship with calibrated FXaI assays, especially at the lower end of on-therapy levels, and they may provide rapid assessment of drug activity for clinical decision making. Currently, there is very limited knowledge of DOAC effect on viscoelastic measurements. Although there is uniformity in expression of DOAC concentrations in nanograms per milliliter, a universal FXaI DOAC assay is urgently needed.
Indolent lymphomas: pushing the pace with novel agents
Authors: Jacobson Caron A. 
Published: December 2019

Abstract
Chemoimmunotherapy has been a hallmark of treatment of indolent B-cell non-Hodgkin lymphomas for the past 2 decades, with high response rates seen but relapses nearly inevitable and patients spending, on average, 20 years on and off treatment. Treatment advances, then, should be aimed at maintaining efficacy while minimizing toxicity or at achieving cure. Improved understanding of the genetic and molecular features of these diseases, as well as of the interaction between the tumor cell and its immune microenvironment, has resulted in an accelerated expansion of tolerable treatment options for patients, with new combinations of therapy holding promise that definitive therapy in these diseases is possible. These drugs include immunomodulating agents such as lenalidomide, small-molecule inhibitors of the B-cell receptor signaling pathway such as ibrutinib and idelalisib, B-cell lymphoma 2 homology 3 mimetics such as venetoclax, and enhancer of zeste homolog 2 inhibitors such as tazemetostat. Therapies that improve the host immune response against the malignant B cell are also of great interest, given the durable remission seen after allogeneic stem cell transplant in these diseases, and immune checkpoint inhibitors, agonist antibodies against immunostimulatory T-cell receptors, antibody–drug conjugates, bispecific antibodies, and finally chimeric antigen receptor T cells are all being investigated, with promising early efficacy signals. These treatments may not necessarily replace chemotherapy but rather augment it in an attempt to improve quality of life and survival for these patients.
Where does transplant fit in the age of targeted therapies?
Authors: Chow Victor A. , Gopal Ajay K. 
Published: December 2019

Abstract
The role of hematopoietic cell transplantation (HCT) for indolent lymphoma has evolved over the last 5 years with the availability of novel low-toxicity therapies and a better understanding of the prognosis of these entities. However, despite numerous treatment options for patients with follicular lymphoma, none are thought to be curative, and many require ongoing therapy with chronic toxicity. Historical trials indicate that autologous HCT as initial consolidation leads to improved progression-free survival, but not overall survival (OS) and, thus, is not typically recommended. However, autologous HCT for chemosensitive relapse can be carried out with ∼1% early mortality risk, affording disease control lasting a median of 3 to 5 years and the potential to improve OS. These results may compare favorably in efficacy, toxicity, and cost vs multiple sequential novel therapies with shorter durations of benefit. Recent data indicate that autologous HCT in follicular lymphoma patients with early initial progression will result in more than one third being alive and without relapse at 5 years, leading to improved OS when used within a year of the first recurrence. Unlike other available therapies, allogeneic HCT has the potential to cure up to one half of those transplanted with indolent B-cell non-Hodgkin lymphoma, although the risks need to be recognized and appropriate patient and donor selection is critical to ensure the best outcomes. HCT continues to remain a viable option in the current era of multiple targeted agents.
New diagnostic tools for delineating iron status
Authors: Ginzburg Yelena Z. 
Published: December 2019

Abstract
Recent advances in our understanding of iron metabolism regulation and crosstalk with erythropoiesis have provided insight into the pathophysiology of multiple disease conditions. For instance, the peptide hormone hepcidin is central to the regulation of iron metabolism. Its effect on cellular iron concentration involves binding ferroportin, the main iron export protein, resulting in its internalization and degradation and leading to iron sequestration within ferroportin-expressing cells. Furthermore, hepcidin regulation by erythropoiesis is attributed in large part to a bone marrow–derived hormone erythroferrone. Erythroferrone-induced hepcidin suppression in diseases of expanded hematopoiesis results in iron overload. Conversely, diseases, such as iron refractory iron deficiency anemia and anemia of chronic inflammation, are characterized by aberrantly increased hepcidin, resulting in iron sequestration and decreased circulating iron and eventually leading to iron-restricted erythropoiesis. Lastly, because iron functions in concert with erythropoietin to promote erythroid precursor survival, proliferation, and differentiation, iron deficiency anemia is a consequence not only of decreased hemoglobin synthesis in each cell but also, a decrease in erythropoietin responsiveness in the bone marrow. How to translate this new information to the clinical setting has not been fully elucidated. The purpose of this manuscript is to summarize current standard tools for identifying iron deficiency in anemic patients; explore the tools and context for evaluating novel markers, such as hepcidin, erythroferrone, and markers of the iron restriction response; and assess available evidence for how their use could increase our understanding of health outcomes in clinically challenging cases.
Diagnostic workflow for hereditary erythrocytosis and thrombocytosis
Authors: McMullin Mary Frances 
Published: December 2019

AbstractIn the patient presenting with an elevated blood count who does not have an acquired clonal disorder causing a myeloproliferative neoplasm, hereditary erythrocytosis or hereditary thrombocytosis needs to be considered as a possible explanation. A young patient and/or those with a family history of myeloproliferative neoplasm should specifically raise this possibility. Among the causes of hereditary erythrocytosis are mutations in the genes in the oxygen sensing pathway and high-affinity hemoglobins. Hereditary thrombocytosis has been shown to be accounted for by mutations in THPO, MPL, and JAK2 genes. In those who have a possible hereditary erythrocytosis or thrombocytosis, the investigative pathway includes specific investigation to rule out the more common acquired clonal disorders, and, if indicated, other secondary causes, measurement of specific cytokines as indicated, and search for specific identified molecular lesions that have been shown to cause these hereditary disorders. There remain individuals who appear to have a hereditary disorder in whom a genetic lesion cannot currently be identified.
Treatment of primary immunodeficiency with allogeneic transplant and gene therapy
Authors: Pai Sung-Yun 
Published: December 2019

Abstract
The treatment of primary immunodeficiency disorders with allogeneic hematopoietic cell transplantation (HCT) has a history dating back to 1968 with the first successful transplant for a patient with severe combined immunodeficiency (SCID). The omission of conditioning for patients with SCID owing to their inability to reject allogeneic grafts and the increasing use of reduced intensity conditioning regimens often result in a state of mixed or split donor-recipient chimerism. The use of gene therapy (GT) via retroviral or lentiviral transduction of autologous CD34+ hematopoietic stem and progenitor cells is expected to correct only a portion of the hematopoietic stem cell compartment. The consequences of partial correction after either form of cellular therapy differ according to how the genetic deficiency affects immune cell development and function. Moreover, the conditioning regimen or lack thereof impacts the cell lineages at risk of partial correction. Advances in our understanding of immune reconstitution after HCT and GT for SCID, Wiskott–Aldrich syndrome, and chronic granulomatous disease are discussed.
Single-agent and combination biologics in acute myeloid leukemia
Authors: Richard-Carpentier Guillaume , DiNardo Courtney D. 
Published: December 2019

AbstractAcute myeloid leukemia (AML) is a heterogeneous malignancy characterized by recurrent genetic, epigenetic, and metabolic abnormalities. As a result of our increasing knowledge of the underlying biology of AML leading to rational drug development, several new targeted agents have been recently added to our therapeutic arsenal. The BCL2 inhibitor venetoclax in combination with low-dose cytarabine (LDAC) or hypomethylating agents (HMAs) is safe and effective in older patients with newly diagnosed AML ineligible for intensive chemotherapy. Glasdegib, a hedgehog pathway inhibitor, may be used in combination with LDAC for the same indication and improves survival compared with LDAC alone. In newly diagnosed, fit, older patients with therapy-related AML or AML with myelodysplasia-related changes, the liposome-encapsulated combination of daunorubicin and cytarabine (CPX-351) has shown superiority over the 7 + 3 regimen. The presence of an IDH1 or IDH2 mutation can be effectively targeted by ivosidenib or enasidenib, respectively. Gemtuzumab ozogamicin improves event-free survival in CD33+ patients with favorable or intermediate-risk cytogenetics. With new targeted agents available, comprehensive genomic characterization of AML at diagnosis and relapse is increasingly necessary to select optimal treatment. Herein, we review the new single-agent and combination biologics (omitting FLT3 inhibitors, which are discussed separately) and provide recommendations on how to best use and manage patients on these regimens in clinical practice.
Patient blood management as the standard of care
Authors: Murphy Michael F. , Palmer Antony 
Published: December 2019

Abstract
Blood transfusion is one of the most common hospital procedures in developed countries. However, inappropriate use of blood transfusion is common, and this is of considerable concern because transfusion is known to be associated with adverse events and is costly. Reductions in blood use have resulted from recent evidence indicating that restrictive use of red blood cell transfusions is associated with similar patient outcomes to liberal strategies and from a focus on patient blood management (PBM), which recognizes the importance of conserving the patient’s own blood alongside the judicious use of transfusion. A recent Consensus Conference in Frankfurt developed practice and research recommendations for PBM but also indicated that additional studies are needed to provide better evidence for PBM interventions, including for improved patient outcomes and lower hospital costs as well as for reductions in blood utilization. In the meanwhile, it is of utmost importance to translate PBM guidelines into practical day-to-day recommendations and encourage their use to make PBM “the standard of care.”
Perioperative management of patients with von Willebrand disease
Authors: O’Donnell James S. , Lavin Michelle 
Published: December 2019

AbstractSurgical procedures represent a serious hemostatic challenge for patients with von Willebrand disease (VWD), and careful perioperative management is required to minimize bleeding risk. Risk stratification includes not only the nature of the surgery to be performed but the baseline plasma von Willebrand factor (VWF) levels, bleeding history, and responses to previous challenges. Baseline bleeding scores (BSs) may assist in identification of patients with a higher risk of postsurgical bleeding. There remains a lack of consensus between best practice guidelines as to the therapeutic target and assays to be monitored in the postoperative period. Hemostatic levels are maintained until bleeding risk abates: usually 3 to 5 days for minor procedures and 7 to 14 days for major surgery. Hemostatic supplementation is more complex in VWD than in other bleeding disorders owing to the combined but variable deficiency of both plasma VWF and factor VIII (FVIII) levels. For emergency surgery, coadministration of VWF and FVIII is required to ensure hemostasis; however, for elective procedures, early infusion of VWF replacement therapy will stabilize endogenous FVIII. Because endogenous FVIII production is unaffected in patients with VWD, repeated VWF supplementation (particularly with plasma-derived FVIII-containing products) may lead to accumulation of FVIII. Frequent monitoring of plasma levels and access to hemostatic testing are, therefore, essential for patients undergoing major surgery, particularly with more severe forms of VWD.
Is there a role for immunosuppression in antiphospholipid syndrome?
Authors: Sevim Ecem , Willis Rohan , Erkan Doruk 
Published: December 2019

AbstractAntiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombosis, pregnancy morbidity, or nonthrombotic manifestations in patients with persistently positive antiphospholipid antibodies (aPL). Conventional APS treatment focuses on antithrombotic strategies, which are usually ineffective for the microvascular and nonthrombotic manifestations of aPL. Using a case-based presentation, this review focuses on the role of immunosuppression in nonobstetric APS, including B-cell inhibition (rituximab, belimumab, and bortezomib), complement inhibition (eculizumab), mechanistic target of rapamycin inhibition (sirolimus), vascular endothelial cell modulation (defibrotide), statins, and traditional rheumatologic disease–modifying agents (hydroxychloroquine, mycophenolate mofetil, azathioprine, and cyclophosphamide).
Evidence-Based Minireview: What is the optimal timing of anti–PD-1 antibodies in relapsed classical Hodgkin lymphoma?
Authors: Allen Pamela Blair , LaCasce Ann S. 
Published: December 2019

Abstract
A 26-year-old woman was initially diagnosed with stage III classical Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for 6 cycles and relapsed 9 months after completing therapy. She was treated with salvage chemotherapy followed by an autologous transplantation and 1 year of brentuximab vedotin (BV) maintenance therapy. She now presents 1 year later with relapsed disease above and below the diaphragm. What treatment would you recommend for this patient?
How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide
Authors: McCurdy Shannon R. , Luznik Leo 
Published: December 2019

Abstract
HLA-haploidentical hematopoietic stem cell transplantation is now one of the most commonly employed alternative donor techniques, with most centers applying T-cell–replete strategies such as that developed by the Baltimore group using high-dose posttransplant cyclophosphamide. HLA-haploidentical hematopoietic stem cell transplantation using posttransplant cyclophosphamide is associated with low rates of severe graft-versus-host disease and nonrelapse mortality and does not require graft manipulation or storage, which results in a low graft acquisition cost. Its remarkable safety when used with reduced-intensity conditioning has been demonstrated in patients up to 75 years old with outcomes similar to those of patients in their 50s. Several large, registry-based retrospective studies have confirmed the efficacy of HLA-haploidentical hematopoietic stem cell transplantation with posttransplant cyclophosphamide, achieving results comparable to those of HLA-matched hematopoietic stem cell transplantation. In this article, we describe our approach to this rapidly available and clinically simple platform and address some of the key clinical questions associated with its use.