bluuebunny/crossref_metadata_2025 huggingface dataset:
Damage modeling and critical damage evaluation of AA2014 cast alloy embedded with fly ash composite under upsetting
Authors: HariKrishna Ch , Davidson MJ
Published: April 2019

Abstract:

Upsetting is one of the primary metal forming techniques and needs to be applied to reduce the cross section of the billets for further processing. Ductile fracture in metal upsetting process is an issue and depends on the material used and processing conditions. The current work focus is on the critical damage evaluation of AA2014 cast alloy embedded with fly ash composite. AA2014 alloy was heated to a pouring temperature of 750 ℃ and fly ash of 3% and 6% were added separately with AA2014 matrix material to prepare three sets of cast alloys namely pure AA2014, AA2014 + 3% fly ash, and AA2014 + 6% fly ash. After manufacturing three sets of rods from stir casting process, three sets of billets were machined to a height and diameter of 24 mm. Three sets of billets were compressed between rigid dies to different levels of strain until the initiation of fracture. Ductile fracture criterions were modeled to evaluate the critical damage value and fracture loci were constructed for different compositions.
Pins and rubbers traction system for fractures of the proximal interphalangeal joint
Authors: Nanno Mitsuhiko , Kodera Norie , Tomori Yuji , Takai Shinro
Published: April 2019

Purpose:

We aimed to evaluate the clinical results using the pins and rubbers traction system (PRTS) as described by Suzuki et al. for unstable intra-articular fractures of the proximal interphalangeal (PIP) joint and to assess the efficacy and the indication of the technique of the PRTS.

Methods:

Thirty-nine fingers in 39 patients (mean age 46.0 years) with unstable fractures of the PIP joint were treated by the PRTS. The mean interval between injury and surgery was 30.8 days. Active and passive exercise of range of motion of all fingers was started immediately after surgery. Radiographic and clinical results were evaluated at the final examination.

Results:

The mean period the PRTS was applied was 6.4 weeks. The mean follow-up period was 8.9 months. Anatomical union was obtained in all patients. No joint instability, no malunion, nor osteomyelitis was observed. At the final examination, the average active range of motion of the PIP joint was 74.6°. The average Visual Analogue Scale for pain and Quick Disability of Arm, Shoulder, and Hand score were 1.2 and 3.2, respectively.

Conclusions:

The current study demonstrated good results of the PRTS for unstable intra-articular fractures of the PIP joint. Furthermore, satisfactory results were obtained in cases of an incomplete amputation at the PIP joint, a pathological fracture due to bone tumor, and an osteochondral defect due to comminuted fracture of the proximal phalangeal head, where costal osteochondral bone was transplanted. From this study, the PRTS is recommended as a useful treatment because it is widely effective for various unstable fractures of the PIP joint.
Incidental venous thromboembolism: is anticoagulation indicated?
Authors: Di Nisio Marcello , Carrier Marc
Published: April 2019

Patients with cancer have a high risk of venous thromboembolism (VTE) and about one-half of these events are incidentally detected. The prognosis of incidental VTE appears to be similar to symptomatic events, with comparably high rates of recurrent VTE in this patient population. In the absence of major contraindications, anticoagulant treatment with low-molecular-weight heparin for 3 to 6 months is generally recommended for incidental proximal deep vein thrombosis as well as for incidental pulmonary embolism that involves multiple subsegmental or more proximal pulmonary arteries. The decision of whether to extend treatment beyond 3 to 6 months should be evaluated on a case-by-case basis after periodic reassessment of the risks factors for bleeding and recurrent VTE while also taking into account patient preferences. The clinical relevance of a single incidental subsegmental pulmonary embolism without concomitant deep vein thrombosis is uncertain and either a watchful approach or a shorter course of anticoagulation to minimize the bleeding risk may also be considered. Preliminary evidence suggests that anticoagulation treatment may be beneficial for cancer patients with incidental distal deep vein thrombosis or incidental splanchnic vein thrombosis.
Thrombocytopenia in pregnancy
Authors: Cines Douglas B. , Levine Lisa D.
Published: April 2019

Thrombocytopenia develops in 5% to 10% of women during pregnancy or in the immediate postpartum period. A low platelet count is often an incidental feature, but it might also provide a biomarker of a coexisting systemic or gestational disorder and a potential reason for a maternal intervention or treatment that might pose harm to the fetus. This chapter reflects our approach to these issues with an emphasis on advances made over the past 5 to 10 years in understanding and managing the more common causes of thrombocytopenia in pregnancy. Recent trends in the management of immune thrombocytopenia translate into more women contemplating pregnancy while on treatment with thrombopoietin receptor agonists, rituximab, or mycophenylate, which pose known or unknown risks to the fetus. New criteria to diagnose preeclampsia, judicious reliance on measurement of ADAMTS13 to make management decisions in suspected thrombotic thrombocytopenic purpura, new evidence supporting the efficacy and safety of anticomplement therapy for atypical hemolytic uremic syndrome during pregnancy, and implications of thrombotic microangiopathies for subsequent pregnancies are evolving rapidly. The goals of the chapter are to help the hematology consultant work through the differential diagnosis of thrombocytopenia in pregnancy based on trimester of presentation, severity of thrombocytopenia, and coincident clinical and laboratory manifestations, and to provide guidance for dealing with some of the more common and difficult diagnostic and management decisions.
Should we diagnose and treat distal deep vein thrombosis?
Authors: Robert-Ebadi Helia , Righini Marc
Published: April 2019

Ultrasound series report that isolated distal deep vein thrombosis (DVT), also known as calf DVT, represents up to 50% of all lower-limb DVTs and, therefore, is a frequent medical condition. Unlike proximal DVT and pulmonary embolism, which have been studied extensively and for which management is well standardized, much less is known about the optimal management of isolated calf DVT. Recent data arising from registries and nonrandomized studies have suggested that most distal DVTs do not extend to the proximal veins and have an uneventful follow-up when left untreated. These data had some impact on the international recommendations that recently stated that ultrasound surveillance instead of systematic therapeutic anticoagulation might be an option for selected low-risk patients. However, robust data from randomized studies are scarce. Only 5 randomized trials assessing the need for anticoagulation for calf DVT have been published. Many of these trials had an open-label design and were affected by methodological limitations. The only randomized placebo-controlled trial included low-risk patients (outpatients without cancer or previous venous thromboembolism [VTE]) and was hampered by limited statistical power. Nevertheless, data from this trial confirmed that the use of therapeutic anticoagulation in low-risk patients with symptomatic calf DVT is not superior to placebo in reducing VTE but is associated with a significantly higher risk of bleeding. Further randomized studies are needed to define the best therapy for high-risk patients (inpatients, patients with active cancer, or patients with previous VTE) and the optimal dose and duration of treatment.
Optimizing therapy for mantle cell lymphoma
Authors: Martin Peter
Published: April 2019

Most people with mantle cell lymphoma (MCL) present with diffuse adenopathy and benefit from early initiation of rituximab and high-dose cytarabine- or bendamustine-based therapies. Some patients, however, present with primarily nonnodal disease that can follow either an indolent or a rapidly progressive, treatment-resistant clinical course. Rarely, patients present with explosive disease that can be challenging to manage and often involves the central nervous system. New agents with improved therapeutic indices facilitate treatment while maintaining quality of life, but also present new complications at the time of treatment failure. Although uncommon presentations are not new to clinicians who treat MCL, the increasing clarity of underlying biology and prognostic implications may help us develop more specialized treatment strategies.
Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma
Authors: Liu W. Robert , Shipp Margaret A.
Published: April 2019

Classical Hodgkin lymphoma (cHL) is an unusual B-cell–derived malignancy in which rare malignant Hodgkin and Reed-Sternberg (HRS) cells are surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. This striking feature suggests that malignant HRS cells escape immunosurveillance and interact with immune cells in the cancer microenvironment for survival and growth. We previously found that cHLs have a genetic basis for immune evasion: near-uniform copy number alterations of chromosome 9p24.1 and the associated PD-1 ligand loci, CD274/PD-L1 and PDCD1LG2/PD-L2, and copy number–dependent increased expression of these ligands. HRS cells expressing PD-1 ligands are thought to engage PD-1 receptor–positive immune effectors in the tumor microenvironment and induce PD-1 signaling and associated immune evasion. The genetic bases of enhanced PD-1 signaling in cHL make these tumors uniquely sensitive to PD-1 blockade.
Emerging role of novel therapies in Hodgkin lymphoma: proceed with caution
Authors: Bartlett Nancy L.
Published: April 2019

Based on very high response rates in the relapsed and refractory setting, brentuximab vedotin and the programmed cell death protein 1 (PD-1) inhibitors, nivolumab and pembrolizumab, have quickly been incorporated into clinical trials for first- and second-line therapy of Hodgkin lymphoma. Preliminary data show that brentuximab vedotin alone is not adequate therapy for newly diagnosed Hodgkin lymphoma in older patients, but modestly decreases the risk of relapse when combined with adriamycin, vinblastine, and dacarbazine in patients with previously untreated advanced-stage disease. In second-line therapy, combining brentuximab vedotin with conventional chemotherapy or with PD-1 inhibitors as pretransplant salvage is associated with high overall and complete response rates, although further follow up is needed to assess whether posttransplant outcomes are improved. Although these new drugs are well tolerated when given as single agents, unexpected toxicities have been encountered with combination regimens, specifically severe pulmonary toxicity with the bleomycin and brentuximab vedotin combination and frequent infusion-related reactions. There is concern with the use of PD-1 inhibitors as first-line therapy due to the theoretical potential for more frequent or severe immune-mediated toxicities in patients who have not received prior chemotherapy. Aside from these concerns, these new agents have the potential to improve outcomes for patients even further, bringing us closer to eradicating recurrent Hodgkin lymphoma.
Optimizing frontline therapy of CLL based on clinical and biological factors
Authors: Fischer Kirsten , Hallek Michael
Published: April 2019

The heterogeneity of the clinical course of chronic lymphocytic leukemia (CLL) ranges from an indolent course, where patients do not require therapy for many years, to a very aggressive disease, where treatment is required soon after diagnosis and relapses may occur early. The improved tools for prognostication allow predicting the outcome of patients with increasing reliability. Some markers also allow selecting more specific therapies with improved activity in the presence of certain genetic or clinical features of CLL. Of these markers, TP53 dysfunction, age, the presence of comorbidities and the immunoglobulin heavy-chain variable region gene mutational status, or serum markers such as β2-microglobulin have shown independent prognostic value in multiple prospective trials. During the last 10 years, multiple novel agents have become available. The advent of oral kinase inhibitors or Bcl-2 antagonists has provided highly effective options with acceptable toxicity. This manuscript summarizes the current evidence of the available treatment options and proposes an integrated algorithm for the frontline therapy of CLL.
How should we sequence and combine novel therapies in CLL?
Authors: Davids Matthew S.
Published: April 2019

With the recent approval of several effective and well-tolerated novel agents (NAs), including ibrutinib, idelalisib, venetoclax, and obinutuzumab, patients with chronic lymphocytic leukemia (CLL) have more therapeutic options than ever before. The availability of these agents is both an important advance for patients but also a challenge for practicing hematologist/oncologists to learn how best to sequence NAs, both with respect to chemoimmunotherapy (CIT) and to other NAs. The sequencing of NAs in clinical practice should be guided both by an individual patient’s prognostic markers, such as FISH and immunoglobulin heavy chain variable region (IGHV)-mutation status, as well as the patient’s medical comorbidities and goals of care. For older, frailer patients with lower-risk CLL prognostic markers, NA monotherapy may remain a mainstay of CLL treatment for years to come. For younger, fitter patients and those with higher-risk CLL, such as del(17p) or unmutated IGHV, combination approaches may prove to be more valuable than NA monotherapy. Trials are currently evaluating the efficacy of several such combination approaches, including NA plus anti-CD20 monoclonal antibody, NA plus NA (with or without anti-CD20 monoclonal antibody), and NA plus CIT. Given the tremendous efficacy of the already approved NAs, as well as the promising data for next generation NAs, the development of well-tolerated, highly effective combination strategies with curative potential for patients with CLL has become a realistic goal.
Toward personalized treatment in Waldenström macroglobulinemia
Authors: Castillo Jorge J. , Treon Steven P.
Published: April 2019

Waldenström macroglobulinemia (WM) is a rare lymphoma with 1000 to 1500 new patients diagnosed per year in the United States. Patients with WM can experience prolonged survival times, which seem to have increased in the last decade, but relapse is inevitable. The identification of recurrent mutations in the MYD88 and CXCR4 genes has opened avenues of research to better understand and treat patients with WM. These developments are giving way to personalized treatment approaches for these patients, focusing on increasing depth and duration of response alongside lower toxicity rates. In the present document, we review the diagnostic differential, the clinical manifestations, and the pathological and genomic features of patients with WM. We also discuss the safety and efficacy data of alkylating agents, proteasome inhibitors, monoclonal antibodies, and Bruton tyrosine kinase inhibitors in patients with WM. Finally, we propose a genomically driven algorithm for the treatment of WM. The future of therapies for WM appears bright and hopeful, but we should be mindful of the cost-effectiveness and long-term toxicity of novel agents.
Advances in the diagnosis and treatment of Von Willebrand disease
Authors: Sharma Ruchika , Flood Veronica H.
Published: April 2019

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, yet diagnosis and management remain challenging. Development and use of bleeding assessment tools allows for improved stratification of which patients may require further assessment and which patients are most likely to require treatment of their VWD. New options for laboratory assessment of von Willebrand factor (VWF) activity include a new platelet-binding assay, the VWF:GPIbM, which is subject to less variability than the ristocetin cofactor activity assay, and collagen-binding assays that provide insight into a different function of VWF. Genetic testing may be helpful in some cases where a type 2 VWD variant is suspected but is usually not helpful in type 1 VWD. Finally, treatment options for VWD are reviewed, including the use of recombinant VWF. Despite these advances, still more work is required to improve diagnosis, treatment, and quality of life for affected patients.
Cardiovascular complications in patients with sickle cell disease
Authors: Gladwin Mark T.
Published: April 2019

Sickle cell disease (SCD) is an autosomal recessive disease in which homozygosity for a single point mutation in the gene encoding the β-globin chain produces hemoglobin S molecules that polymerize within the erythrocyte during deoxygenation; the result is sustained hemolytic anemia and vaso-occlusive events. As patients live to adulthood, the chronic impact of sustained hemolytic anemia and episodic vaso-occlusive episodes leads to progressive end-organ complications. This scenario culminates in the development of 1 or more major cardiovascular complications of SCD for which there are no approved or consensus therapies. These complications include elevated pulmonary artery systolic pressure, pulmonary hypertension, left ventricular diastolic heart disease, dysrhythmia, sudden death, and chronic kidney disease with associated proteinuria, microalbuminuria, and hemoglobinuria. In patients with advancing age, cardiopulmonary organ dysfunction and chronic kidney injury have significant effects on morbidity and premature mortality. Over the last 15 years, a number of tests have been validated in multiple replicate cohort studies that identify patients with SCD at the highest risk of experiencing pulmonary and systemic vasculopathy and death, providing for screening strategies tied to targeted, more aggressive diagnostic and therapeutic interventions.
Management of multiple myeloma in the newly diagnosed patient
Authors: Mateos María-Victoria , San Miguel Jesús F.
Published: April 2019

Multiple myeloma is the second most frequent hematological disease. The introduction of melphalan as high-dose therapy followed by autologous hematopoietic cell transplantation (HDT/ASCT) for young patients and the availability of novel agents for young and elderly patients with multiple myeloma have dramatically changed the perspective of treatment. However, further research is necessary if we want definitively to cure the disease. Treatment goals for transplant-eligible and non–transplant-eligible patients should be to prolong survival by achieving the best possible response while ensuring quality of life. For young patients, HDT-ASCT is a standard of care for treatment, and its efficacy has been enhanced and challenged by the new drugs. For elderly patients, treatment options were once limited to alkylators, but new upfront treatment combinations based on novel agents (proteasome inhibitors and immunomodulatory drugs) combined or not with alkylators have significantly improved outcomes. Extended treatment of young and elderly patients improves the quality and duration of clinical responses; however, the optimal scheme, appropriate doses, and duration of long-term therapy have not yet been fully determined. This review summarizes progress in the treatment of patients with newly diagnosed multiple myeloma, addressing critical questions such as the optimal induction, early vs late ASCT, consolidation and/or maintenance for young patients, and how we can choose the best treatment option for non–transplant-eligible patients.
The role of targeted therapy in the management of patients with AML
Authors: Perl Alexander E.
Published: April 2019

Drug therapy for acute myeloid leukemia (AML) is finally undergoing major changes in 2017. This is due to the US Food and Drug Administration’s approval of several new, targeted agents (midostaurin, enasidenib, and gemtuzumab ozogamicin). Paired with the recent approval of a novel liposomal formulation of daunorubicin/cytarabine (CPX-351/Vyxeos), the standard of care is changing rapidly in AML for subgroups. This review will focus on currently approved agents and promising novel agents in development and will highlight controversial areas in targeted treatment.
Responsiveness of Patient-Reported Outcome Measurement Information System (PROMIS) pain domains and disease-specific patient-reported outcome measures in children and adults with sickle cell disease
Authors: Curtis Susanna , Brandow Amanda M.
Published: April 2019

Case 1: A 33-year-old man with hemoglobin SS (homozygous hemoglobin S) disease presents for his regular clinic visit. He had 6 hospital admissions for pain over the past year. He also has avascular necrosis of the right hip. He takes daily hydroxyurea with hematologic changes indicative of compliance. He also takes morphine sustained release twice daily and morphine immediate release every 6 hours as needed for pain. He feels that more optimal pain control at home would help him reduce his number of hospital admissions in the upcoming year and improve his daily functioning at home. His hematologist decides to use Patient-Reported Outcome Measurement Information System (PROMIS) and Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-ME) to follow changes in the patient’s pain. Case 2: An 11-year-old girl with hemoglobin SS disease presents with her mother for her regular clinic visit. She had 2 admissions for pain over the past year. Her mother is concerned because she has been participating less in activities she previously enjoyed and missing classes to go to the school nurse because of pain. She is currently taking hydroxyurea and uses ibuprofen for pain. Her doctor prescribes morphine for home use but wants a way to measure if it is effective in improving her pain. Thus, her physician decides to use PROMIS and the Pediatric Quality of Life Inventory SCD (PedsQL SCD) module to determine the effectiveness of her pain control.
Using pharmacokinetics to individualize hemophilia therapy
Authors: Iorio Alfonso
Published: April 2019

Prevention and treatment of bleeding in hemophilia requires that plasma clotting factor activity of the replaced factor exceeds a defined target level. Most clinical decisions in hemophilia are based on implicit or explicit application of pharmacokinetic measures. The large interindividual variability in pharmacokinetics of factor concentrates suggests that relying on the average pharmacokinetic characteristics of factor concentrates would not allow optimizing the treatment of individual patients; for example, adjusting the frequency of infusions and targeting a specific clotting factor activity level on a case-by-case basis. However, individual pharmacokinetic profiles are seldom assessed as part of routine clinical care. Population pharmacokinetics provide options for precise and convenient characterization of pharmacokinetics characteristics of factor concentrates, simplified individual pharmacokinetic profiling, and individualized dosing. Population pharmacokinetics allow for the incorporation of determinants of interpatient variability and reduces the need for extensive postinfusion plasma sampling. Barriers to the implementation of population pharmacokinetics are the need for concentrate-specific pharmacokinetic models, Bayesian calculation power, and specific expertise for production, validation, and appraisal of forecasted estimates. Population pharmacokinetics provide an important theoretical and practical contribution to tailoring the treatment of hemophilia. The need remains for prospective exploration of the clinical impact of tailoring hemophilia treatment based on individual pharmacokinetics, and for the systematic validation of existing software solutions and concentrate-specific models.
Anticoagulation with VADs and ECMO: walking the tightrope
Authors: Raffini Leslie
Published: April 2019

The evolution of devices for mechanical circulatory support (MCS), including ventricular assist devices (VADs) for patients with heart failure and extracorporeal membrane oxygenation (ECMO) for patients with acute cardiac or respiratory failure, has improved survival for subsets of critically ill children and adults. The devices are intricate and complex, allowing blood to bypass the heart or lungs (or both). As blood flows through these artificial devices, normal hemostasis is disrupted, coagulation is promoted, and in the absence of anticoagulation, a thrombus may form in the device, resulting in device failure or embolic stroke. Therefore, anticoagulation is necessary to prevent thrombus formation and maintain device function. However, patients on MCS also have very high bleeding rates. Titrating anticoagulation to prevent hemorrhagic complications and thrombotic events can be a challenge, and hematologists may be consulted in complex cases. Substantial variability remains in the approach to anticoagulant and antiplatelet therapy for patients on MCS, largely because of the lack of high-quality data. Improvements in the design and manufacture of these devices, as well as in the individualized titration of antithrombotic intensity, are expected to enhance outcomes. Several factors pertaining to both the device and the patient (adult and children) should be considered when attempting to optimize this delicate balance.
Inherited bone marrow failure syndromes: considerations pre- and posttransplant
Authors: Alter Blanche P.
Published: April 2019

Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome. This review discusses the major complications that develop as the patients with these syndromes age, as well as additional late effects following hematopoietic stem cell transplantation. The most common complications are iron overload in transfused patients and syndrome-specific malignancies in untransplanted patients, which may occur earlier and with higher risks in those who have received transplants.
On the architecture of translational research designed to control chronic lymphocytic leukemia
Authors: Hallek Michael
Published: April 2019

Chronic lymphocytic leukemia (CLL) has been 1 of the most dynamic fields of clinical research over the last 2 decades. Important advances in understanding the biology of CLL have led to the development of new prognostic and diagnostic tools. Concurrently, several recently approved new agents hold the potential to fundamentally change the management of this leukemia and have started to improve clinical outcomes for patients. This conceptual review summarizes the major recent insights regarding the biology of CLL, the technological advances that have allowed refinement of the prognostication of the clinical course, and the new therapeutic strategies that are currently under investigation to further ameliorate the outcome for patients with CLL.
Case-based roundtable on treatment approach for young, fit, newly diagnosed multiple myeloma patients
Authors: Giralt Sergio , Seifter Eric
Published: April 2019

With the advent new proteasome inhibitors (carfilzomib, ixazomib), new immune-modulatory drugs (pomalidomide), and new monoclonal antibodies (elotuzimab, daratumumab) as approved treatments for myeloma, the therapeutic landscape for this disease has changed. In this chapter, using a case-based approach, I will provide a personal guide of how I approach myeloma therapy in a transplant eligible patient in 2018.
Molecular monitoring in CML: how deep? How often? How should it influence therapy?
Authors: Shanmuganathan Naranie , Hughes Timothy P.
Published: April 2019

With the advent of tyrosine kinase inhibitors (TKIs), the goals of therapy in chronic myeloid leukemia (CML) are steadily shifting. Long-term disease control on TKI therapy has been the goal and expectation for most patients. More recently, treatment-free remission (TFR) has entered mainstream practice and is increasingly being adopted as the main goal of therapy. This therapeutic shift not only influences TKI selection but also, has necessitated the refinement and dissemination of highly sensitive and accurate molecular monitoring techniques. Measurement of BCR-ABL1 messenger RNA expression through reverse transcription quantitative polymerase chain reaction, reported according to the International Scale, has become the primary tool for response assessment in CML. Achieving specific time-dependent molecular milestones, as defined by global therapeutic guidelines, has been established as critical in maximizing optimal outcomes while identifying patients at risk of therapy failure. Depth and duration of a deep molecular response have become the new therapeutic targets in patients considered for TFR. Consequently, molecular monitoring in CML has become even more critical to ongoing response assessment, identifying patients with TKI resistance and poor drug adherence, and enabling TFR to be attempted safely and effectively.
Novel immunotherapy approaches to follicular lymphoma
Authors: Flowers Christopher R. , Leonard John P. , Nastoupil Loretta J.
Published: April 2019

Follicular lymphoma (FL) remains a lymphoma subtype that is remarkably sensitive to immunotherapy-based treatment strategies. Anti-CD20 antibody therapy administered as a single agent and in combination as a first-line treatment and at relapse continues to be the most broadly used therapy for this disease. Autologous and allogeneic stem cell transplantation provide meaningful durable remissions for patients with FL. However, identifying the most suitable patients and the optimal timing for these approaches has become increasingly challenging with the advent of novel therapies. Lenalidomide and phosphatidylinositol 3-kinase inhibitors are emerging as agents that can be applied in the relapsed setting. Other immunotherapy approaches, including checkpoint inhibitors and chimeric antigen receptor T cells, appear promising but remain experimental. Utilization of all forms of immunotherapy requires careful consideration of the unique toxicities associated with these agents and the means to mitigate them by selection of appropriate patients, optimal timing, and the use of supportive care.
Where does PD-1 blockade fit in HL therapy?
Authors: Herrera Alex F.
Published: April 2019

Genetic alterations of the PD-L1/PD-L2 locus on chromosome 9p24.1 are a defining biological feature of classical Hodgkin lymphoma (HL). The resulting programmed death-ligand 1 (PD-L1) expression on Hodgkin Reed-Sternberg cells as well as the PD-L1 expressed in the HL microenvironment result in an ineffective host antitumor immune response and make HL a ripe target for programmed cell death-1 (PD-1) blockade. Anti–PD-1 antibody monotherapy has been effective and well tolerated in patients with relapsed or refractory (rel/ref) HL, with the majority of patients experiencing an objective response (approximately two-thirds of patients) and a median duration of response of 16.6 months in the study with the longest follow-up. Based on these data, nivolumab and pembrolizumab were approved by the US Food and Drug Administration (FDA) for the treatment of advanced rel/ref HL. Evidence has emerged that patients with HL benefit from continued PD-1 blockade beyond disease progression according to traditionally defined response criteria, and that the addition of, or switch to, chemotherapy after anti–PD-1 antibody failure can potentially re-induce clinical response. Subsequent studies have evaluated novel anti–PD-1–based combination regimens as well as the use of anti–PD-1 antibody therapy earlier in the course of a HL patient’s therapy, including first salvage therapy for rel/ref disease (eg, nivolumab plus brentuximab vedotin) and even first-line treatment (eg, nivolumab added to doxorubicin, vinblastine, dacarbazine chemotherapy). The current role of PD-1 blockade in HL is as monotherapy in patients with advanced rel/ref disease, but the results of ongoing studies and the evolving treatment landscape in HL will determine the role of PD-1 blockade in the future.
Selecting Frontline Therapy for CLL in 2018
Authors: Jain Nitin
Published: April 2019

The treatment landscape of chronic lymphocytic leukemia (CLL) has changed dramatically in the last few years. The role of chemoimmunotherapy has declined significantly for patients with CLL. Fludarabine, cyclophosphamide, rituximab chemotherapy remains the standard frontline therapy for young fit patients with CLL, especially if IGHV mutated. For older adults, ibrutinib has been shown to be superior to chlorambucil. Hence, the role of chlorambucil monotherapy in the current era in the management of CLL is limited. The combination of chlorambucil and obinutuzumab is an alternative option for patients with comorbidities. For patients with del(17p), ibrutinib has become the standard treatment in the frontline setting. Several phase 3 trials with novel targeted agents, either as monotherapy or in combination, are either ongoing or have completed accrual. The results of many of these trials are expected in the next 1 to 2 years, and they will further help refine the frontline treatment strategy.
Relapsed CLL: sequencing, combinations, and novel agents
Authors: Brown Jennifer R.
Published: April 2019

Although the therapy of chronic lymphocytic leukemia (CLL) has changed rapidly over the last 5 years, the key considerations in selecting a therapy for a previously treated patient with CLL continue to include the nature of the prior therapy and the duration of prior remission to that therapy, the prognostic features of the disease, and the health and comorbidities of the patient in question. For patients treated initially with chemoimmunotherapy, randomized trials have demonstrated the benefit of targeted therapy. Retrospective data suggest that ibrutinib is preferred as a first kinase inhibitor, whereas recent data with venetoclax and rituximab may challenge the choice of ibrutinib as a first novel agent in the relapsed setting. Data on sequencing of novel agents remain quite sparse, consisting of 1 prospective trial that demonstrated the efficacy of venetoclax in patients who have experienced progression with a kinase inhibitor, as well as a retrospective real-world analysis supporting this observation. Novel agents in advanced clinical development include primarily next-generation Bruton’s tyrosine kinase and phosphatidylinositol 3-kinase δ inhibitors, with other classes still in phase 1 trials. Clinical trials of combination time-limited therapies with the goal of deep remission and discontinuation are also in progress.
Using genomics to define pediatric blood cancers and inform practice
Authors: Rau Rachel E. , Loh Mignon L.
Published: April 2019

Over the past decade, there has been exponential growth in the number of genome sequencing studies performed across a spectrum of human diseases as sequencing technologies and analytic pipelines improve and costs decline. Pediatric hematologic malignancies have been no exception, with a multitude of next generation sequencing studies conducted on large cohorts of patients in recent years. These efforts have defined the mutational landscape of a number of leukemia subtypes and also identified germ-line genetic variants biologically and clinically relevant to pediatric leukemias. The findings have deepened our understanding of the biology of many childhood leukemias. Additionally, a number of recent discoveries may positively impact the care of pediatric leukemia patients through refinement of risk stratification, identification of targetable genetic lesions, and determination of risk for therapy-related toxicity. Although incredibly promising, many questions remain, including the biologic significance of identified genetic lesions and their clinical implications in the context of contemporary therapy. Importantly, the identification of germ-line mutations and variants with possible implications for members of the patient’s family raises challenging ethical questions. Here, we review emerging genomic data germane to pediatric hematologic malignancies.
Ethical conundrums in pediatric genomics
Authors: Rotz Seth J. , Kodish Eric
Published: April 2019

Recent genomic discoveries have improved our understanding of many hematologic diseases and led to novel therapeutic options for many patients. The rapid decrease in the cost of genomic testing has enabled widespread use of clinical genomic testing. However, these advances are accompanied by concomitant challenging ethical concerns. In pediatrics, issues of informed consent for genomic testing, assent, and permission vary significantly by patient age and comprehension. Broader testing strategies, such as whole-exome or whole-genome sequencing, are more likely to yield incidental findings unrelated to the reason for the initial test, and plans to deal with these results when they occur are increasingly important. The lines of clinical care and research are becoming more blurry in the era of precision medicine in which approaches to individual genetic mutations (as opposed to disease phenotypes) occur with increased frequency. Finally, because justice is a fundamental ethical consideration, access to genomic testing and a rigorous approach to utility are critical to individual patients and the field of hematology. In this review, we use 3 cases of genomic testing in pediatric hematology to illustrate core ethical concerns and explore potential solutions.
Drug-drug interactions in an era of multiple anticoagulants: a focus on clinically relevant drug interactions
Authors: Vazquez Sara R.
Published: April 2019

Oral anticoagulants are commonly prescribed but high risk to cause adverse events. Skilled drug interaction management is essential to ensure safe and effective use of these therapies. Clinically relevant interactions with warfarin include drugs that modify cytochrome 2C9, 3A4, or both. Drugs that modify p-glycoprotein may interact with all direct oral anticoagulants, and modifiers of cytochrome 3A4 may interact with rivaroxaban and apixaban. Antiplatelet agents, nonsteroidal anti-inflammatory drugs, and serotonergic agents, such as selective serotonin reuptake inhibitors, can increase risk of bleeding when combined with any oral anticoagulant, and concomitant use should be routinely assessed. New data on anticoagulant drug interactions are available almost daily, and therefore, it is vital that clinicians regularly search interaction databases and the literature for updated management strategies. Skilled drug interaction management will improve outcomes and prevent adverse events in patients taking oral anticoagulants.
When to obtain genomic data in acute myeloid leukemia (AML) and which mutations matter
Authors: Roloff Gregory W. , Griffiths Elizabeth A.
Published: April 2019

Mutational profiling has fundamentally changed our approach to patients with acute myeloid leukemia (AML). Patients with AML are routinely profiled for the presence of mutations in FLT3, NPM1, CEBPA, and, more recently, TP53. In this chapter, we review the role of mutational profiling to help define disease biology in AML, particularly among patients with putatively intermediate-risk disease. We describe the body of evidence supporting the utility of mutational profiling when performed at the time of diagnosis (to identify prognostic and targetable mutations), at the time of complete remission (to assess minimal residual disease as a marker for relapse), and at the time of relapse (to identify therapeutic targets and eligibility for clinical trials). We further identify particular mutations that have been shown to affect prognosis across the established European LeukemiaNet risk categories and discuss which mutational events might be used to alter the approach to patient care at various time points during the disease course. We also review the evidence in support of molecular profiling for assessment of minimal/measurable residual disease and describe the current landscape of studies designed to validate this approach.
Who should get long-term anticoagulant therapy for venous thromboembolism and with what?
Authors: Rodger Marc Alan , Le Gal Gregoire
Published: April 2019

After an initial 3 to 6 months of anticoagulation for venous thromboembolism (VTE), clinicians and patients face an important question: “Do we stop anticoagulants or continue them indefinitely?” The decision is easy in some scenarios (eg, stop in VTE provoked by major surgery). In most scenarios, which are faced on a day-to-day basis in routine practice, it is a challenging decision because of uncertainty in estimates in the long-term risks (principally major bleeding) and benefits (reducing recurrent VTE) and the tight trade-offs between them. Once the decision is made to continue, the next question to tackle is “Which anticoagulant?” Here again, it is a difficult decision because of the uncertainty with regard to estimates of efficacy and the safety of anticoagulant options and the tight trade-offs between choices. We conclude with the approach that we take in our clinical practice.
Breadth of complications of long-term oral anticoagulant care
Authors: Ageno Walter , Donadini Marco
Published: April 2019

The majority of patients with venous thromboembolism (VTE) have a considerable long-term risk of recurrence and may require extended duration of anticoagulant treatment after the initial 3 to 6 months. The decision to extend treatment is based not only on the individual risk of recurrence, but should also consider the potential complications associated with anticoagulation, taking into account that anticoagulant drugs are among the drugs most frequently associated with hospital admission due to adverse drug reactions. The most feared complication of oral anticoagulants is bleeding, which in some cases may be fatal or may affect critical organs. Case-fatality rates of bleeding have been reported to be ∼3 times higher than case-fatality rates of recurrent VTE. Even when nonserious, bleeding may require medical intervention and/or may impact on patient quality of life or working activity. Factors associated with bleeding during anticoagulant treatment include, among others, advanced age, cancer, renal or liver insufficiency, or concomitant antithrombotic drugs, but no bleeding risk score is sufficiently accurate for use in clinical practice. Not uncommonly, bleeding occurs as a complication of trauma or medically invasive procedures. Nonbleeding complications associated with oral anticoagulants are unusual, and their relevance is extremely uncertain, and include vascular calcification, anticoagulation-related nephropathy, and osteoporosis. Finally, because VTE not uncommonly affects young individuals and the mean age of the population is ∼60 years, the costs associated with extended anticoagulation should not be forgotten. The costs of the drugs need to be balanced against health outcome costs associated with both recurrent VTE and bleeding.
New drugs for acute myeloid leukemia inspired by genomics and when to use them
Authors: Pollyea Daniel A.
Published: April 2019

We are several years into the “postdiscovery” era in acute myeloid leukemia (AML) thanks to extensive work involving the sequencing of genomes and exomes of countless patients, which has led to routine comprehensive targeted sequencing in clinical care. The ability to unlock the molecular underpinnings of each patient’s disease was supposed to usher in a new treatment era in which each patient was assigned, based on her mutational profile, a personalized cocktail of targeted therapies that would snuff the disease into submission with minimal toxicity. Whether we have fully realized the promise of personalized therapy in AML is unclear. Here, I review those new drugs that have been inspired by genomics, discuss others that might be possible and their potential roles, and consider whether the ability to target genomic mutations in a personalized manner constitutes the future of AML therapeutics or is representative of an era that has already passed.
Activity of eltrombopag in severe aplastic anemia
Authors: Scheinberg Phillip
Published: April 2019

Since the approval of horse antithymocyte globulin (ATG) decades ago, there was a long hiatus in therapies with activity in severe aplastic anemia (SAA). This scenario changed in 2014 when eltrombopag, a thrombopoietin receptor agonist, was approved for SAA after an insufficient response to initial immunosuppressive therapy (IST). The basis for this approval was the observation of single-agent activity of eltrombopag in this patient population, where 40% to 50% recovered blood counts at times involving >1 lineage. The achievement of transfusion independence confirmed the clinical benefit of this approach. Increase in marrow cellularity and CD34+ cells suggested a recovery to a more functioning bone marrow. Further in its development, eltrombopag was associated with standard horse ATG plus cyclosporine in first line, producing increases in overall (at about 90%) and complete response rates (at about 40%) and leading to transfusion independence and excellent survival. Interestingly, best results were observed when all drugs were started simultaneously. The cumulative incidence of clonal cytogenetic abnormalities to date has compared favorably with the vast experience with IST alone in SAA. Longer follow-up will help in define these long-term risks. In this review, the development of eltrombopag in SAA will be discussed.
Cytotoxic therapy in acute myeloid leukemia: not quite dead yet
Authors: Michaelis Laura C.
Published: April 2019

Given the recent approvals of new agents for acute myeloid leukemia (AML), a clinical trial pipeline stocked with novel therapies, and the rapid integration of imaginative approaches in diseases like acute lymphocytic leukemia and chronic lymphocytic leukemia, it is reasonable to ask whether treatment of AML might finally depart from the classical cytotoxic induction therapy that has been employed since the 1970s. However, for better or worse, in 2018, cytotoxic induction regimens remain the standard of care for most patients. Indeed, the future likely lies in combinations of therapies that act with a spectrum of mechanisms. Using a case-based format, this review will outline current treatment expectations for patients according to karyotypic risk and familiarize readers with the basis for common induction choices. Relapsed/refractory disease may be especially amenable to interventions with novel agents or clinical trials; however, there are still some patients who most benefit from intensive chemotherapy. This review will outline risk systems that help the practitioner identify those with the best chances for response and survival. Finally, clinical tools, including geriatric assessments and comorbidity calculators, may help clinicians recognize patients for whom disease risk and comorbidity tip the balance against classical chemotherapy, a frequent challenge for those who treat this devastating disease.