bluuebunny/crossref_metadata_2025 huggingface dataset:
Shall we treat smoldering multiple myeloma in the near future?
Authors: Landgren Ola
Published: April 2019

In recent years, several new drugs have been approved for the treatment of multiple myeloma. Many of these newer drugs are highly efficacious and less toxic than older chemotherapy drugs. In 2014, the diagnostic criteria for multiple myeloma were revised. The intent with the new criteria was to identify patients who require therapy at an earlier stage than at manifestation of organ complications. A subset of patients who were previously defined as having high-risk smoldering multiple myeloma was redefined as having multiple myeloma. In this context, it is logical to raise questions regarding the optimal clinical management of patients who are diagnosed with smoldering multiple myeloma in the current era. When is the optimal time to start therapy? Do the clinical trajectories for patients suggest there are distinct sub-entities hidden in the current category of smoldering multiple myeloma? How can we move the field forward from here? This paper reviews and dissects data and models on the topics of clinical features, underlying biology, and early treatment trials in smoldering multiple myeloma. The text highlights assumptions, facts, and gaps in the literature. As indicated in the title of the paper, the recurrent theme of the text is this: shall we treat smoldering multiple myeloma in the near future?
Current management of Philadelphia chromosome positive ALL and the role of stem cell transplantation
Authors: Ravandi Farhad
Published: April 2019

Treatment of Philadelphia chromosome positive acute lymphoblastic leukemia exemplifies how the addition of potent targeted agents, directed at the molecular aberrations responsible for leukemic transformation, can overcome resistance mechanisms to traditional regimens and lead to improved outcomes. The introduction of BCR-ABL1 targeted tyrosine kinase inhibitors (TKIs) has significantly improved the outcomes not only by allowing more patients to undergo allogeneic hematopoietic cell transplantation (alloHCT) but also by decreasing our reliance on this potentially toxic strategy, particularly in the less fit population. Long-term data using chemotherapy and TKI combinations demonstrate that a proportion of patients treated can achieve durable relapse-free survival without undergoing alloHCT. Furthermore, the availability of sensitive minimal residual disease monitoring assays may allow early detection of the patients who are more likely to relapse and who are likely candidates for early alloHCT. The emergence of more potent TKIs with significant activity against resistant mutations has allowed deintensification of chemotherapy regimens. Available data indicate that complete reliance on TKIs, alone or with minimal additional therapy, and elimination of more intensive chemotherapy or alloHCT is unlikely to achieve long term cure in most patients. However, introduction of other highly effective agents that can be combined with TKIs may allow further minimization of chemotherapy and alloHCT in the future, as we have witnessed in acute promyelocytic leukemia.
Pediatric leukemia susceptibility disorders: manifestations and management
Authors: McReynolds Lisa J. , Savage Sharon A.
Published: April 2019

The clinical manifestations of inherited susceptibility to leukemia encompass a wide phenotypic range, including patients with certain congenital anomalies or early-onset myelodysplastic syndrome (MDS) and some with no obvious medical problems until they develop leukemia. Leukemia susceptibility syndromes occur as a result of autosomal dominant, autosomal recessive, or X-linked recessive inheritance, or de novo occurrence, of germline pathogenic variants in DNA repair, ribosome biogenesis, telomere biology, hematopoietic transcription factors, tumor suppressors, and other critical cellular processes. Children and adults with cytopenias, MDS, dysmorphic features, notable infectious histories, immunodeficiency, certain dermatologic findings, lymphedema, unusual sensitivity to radiation or chemotherapy, or acute leukemia with a family history of early-onset cancer, pulmonary fibrosis, or alveolar proteinosis should be thoroughly evaluated for a leukemia susceptibility syndrome. Genetic testing and other diagnostic modalities have improved our ability to identify these patients and to counsel them and their family members for subsequent disease risk, cancer surveillance, and therapeutic interventions. Herein, the leukemia susceptibility syndromes are divided into 3 groups: (1) those associated with an underlying inherited bone marrow failure syndrome, (2) disorders in which MDS precedes leukemia development, and (3) those with a risk primarily of leukemia. Although children are the focus of this review, it is important for clinicians to recognize that inherited susceptibility to cancer can present at any age, even in older adults; genetic counseling is essential and prompt referral to experts in each syndrome is strongly recommended.
Incorporation of nonchemotherapeutic agents in pediatric acute lymphoblastic leukemia
Authors: Silverman Lewis B.
Published: April 2019

With current available therapies, the prognosis for most children and adolescents with acute lymphoblastic leukemia (ALL) is favorable. However, the multiagent chemotherapy regimens used to treat newly diagnosed patients are associated with many acute and long-term complications, and therapy for relapsed disease is intensive and suboptimally effective. Over the last decade, several nonchemotherapeutic approaches have been evaluated, with the goal of identifying more effective, less toxic therapies that can be used in conjunction with, or even replace, current regimens. Novel nonchemotherapeutic therapies with activity in ALL include (1) tyrosine kinase inhibitors in high-risk patient subsets in whom potentially targetable alterations have been identified and (2) immunotherapeutic approaches, such as monoclonal antibodies, immunotoxins, bispecific T-cell–engaging antibodies, and chimeric antigen receptor T cells. This review summarizes promising results from recent clinical trials of these novel treatments.
Nodular lymphocyte-predominant Hodgkin lymphoma: a unique disease deserving unique management
Authors: Eichenauer Dennis A. , Engert Andreas
Published: April 2019

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity with an incidence of 0.1 to 0.2/100 000/y. Compared with the more common subtypes of classical Hodgkin lymphoma, NLPHL is characterized by distinct pathological and clinical features. Histologically, the disease-defining lymphocyte predominant cells consistently express CD20 but lack CD30. Clinically, NLPHL mostly has a rather indolent course, and patients usually are diagnosed in early stages. The prognosis of early-stage NLPHL is excellent, with progression-free survival and overall survival rates exceeding 90% after involved-field radiotherapy (IF-RT) alone (stage IA) or combined modality treatment consisting of a brief chemotherapy with 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy followed by IF-RT (early stages other than stage IA). In contrast, patients with advanced disease at diagnosis tend to relapse either with NLPHL histology or with histological transformation into aggressive B-cell non-Hodgkin lymphoma despite more aggressive first-line treatment with 6 to 8 cycles of multiagent chemotherapy. However, even NLPHL patients with multiple relapses successfully respond to salvage therapy in many cases. Salvage therapies range from single-agent anti-CD20 antibody treatment to high-dose chemotherapy followed by autologous stem cell transplantation. Treatment at disease recurrence should be chosen on the basis of various factors, including histology at relapse, time to relapse, extent of disease at relapse, and prior treatment. Because death among NLPHL patients is more often caused by therapy-related late effects than lymphoma-related complications, optimizing the risk-benefit ratio of treatment by decreasing toxicity whenever possible is the major goal of clinical research in this disease.
The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment
Authors: Gaidano Gianluca , Rossi Davide
Published: April 2019

The typical genome of chronic lymphocytic leukemia (CLL) carries ∼2000 molecular lesions. Few mutations recur across patients at a frequency >5%, whereas a large number of biologically and clinically uncharacterized genes are mutated at lower frequency. Approximately 80% of CLL patients carry at least 1 of 4 common chromosomal alterations, namely deletion 13q14, deletion 11q22-23, deletion 17p12, and trisomy 12. Knowledge of the CLL genome has translated into the availability of molecular biomarkers for prognosis and treatment prediction. Prognostic biomarkers do not affect treatment choice, and can be integrated into prognostic scores that are based on both clinical and biological variables. Molecular predictive biomarkers affect treatment choice, and currently include TP53 disruption by mutation and/or deletion and IGHV mutation status. TP53 disruption by gene mutation and/or deletion associates with chemoimmunotherapy failure and mandates treatment with innovative drugs, including ibrutinib, idelalisib, or venetoclax. The mutation status of IGHV genes represents a predictive biomarker for identifying patients that may benefit the most from chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. Assessment of these biomarkers at the time of treatment requirement is recommended by most current guidelines for CLL management. Other molecular predictors are under investigation, but their application in clinical practice is premature.
Classification and risk assessment in AML: integrating cytogenetics and molecular profiling
Authors: Moarii Matahi , Papaemmanuil Elli
Published: April 2019

In recent years, the composite molecular architecture in acute myeloid leukemia (AML) has been mapped out. We now have a clearer understanding of the key genetic determinants, the major genetic interactions, and the broad order in which these mutations occur. The next impending challenge is to discern how these recent genomic discoveries define disease biology as well as how to use molecular markers to deliver patient-tailored clinical decision support.
Hereditary thrombocytopenias: a growing list of disorders
Authors: Noris Patrizia , Pecci Alessandro
Published: April 2019

The introduction of high throughput sequencing (HTS) techniques greatly improved the knowledge of inherited thrombocytopenias (ITs) over the last few years. A total of 33 different forms caused by molecular defects affecting at least 32 genes have been identified; along with the discovery of new disease-causing genes, pathogenetic mechanisms of thrombocytopenia have been better elucidated. Although the clinical picture of ITs is heterogeneous, bleeding has been long considered the major clinical problem for patients with IT. Conversely, the current scenario indicates that patients with some of the most common ITs are at risk of developing additional disorders more dangerous than thrombocytopenia itself during life. In particular, MYH9 mutations result in congenital macrothrombocytopenia and predispose to kidney failure, hearing loss, and cataracts, MPL and MECOM mutations cause congenital thrombocytopenia evolving into bone marrow failure, whereas thrombocytopenias caused by RUNX1, ANKRD26, and ETV6 mutations are characterized by predisposition to hematological malignancies. Making a definite diagnosis of these forms is crucial to provide patients with the most appropriate treatment, follow-up, and counseling. In this review, the ITs known to date are discussed, with specific attention focused on clinical presentations and diagnostic criteria for ITs predisposing to additional illnesses. The currently available therapeutic options for the different forms of IT are illustrated.
Five lessons learned about long-term pain management in adults with sickle cell disease
Authors: Field Joshua J.
Published: April 2019

Chronic pain affects one-half of adults with sickle cell disease (SCD). Despite the prevalence of chronic pain, few studies have been performed to determine the best practices for this patient population. Although the pathophysiology of chronic pain in SCD may be different from other chronic pain syndromes, many of the guidelines outlined in the pain literature and elsewhere are applicable; some were consensus-adopted in the 2014 National Heart, Lung, and Blood Institute SCD Guidelines. Recommended practices, such as controlled substance agreements and monitoring of urine, may seem unnecessary or counterproductive to hematologists. After all, SCD is a severe pain disorder with a clear indication for opioids, and mistrust is already a major issue. The problem, however, is not with a particular disease but with the medicines, leading many US states to pass broad legislation in attempts to curb opioid misuse. These regulations and other key tenets of chronic pain management are not meant to deprive adults with SCD of appropriate therapies, and their implementation into hematology clinics should not affect patient-provider relationships. They simply encourage prudent prescribing practices and discourage misuse, and should be seen as an opportunity to more effectively manage our patient’s pain in the safest manner possible. In line with guideline recommendations as well as newer legislation, we present five lessons learned. These lessons form the basis for our model to manage chronic pain in adults with SCD.
Evolving treatment paradigms in sickle cell disease
Authors: Jagadeeswaran Ramasamy , Rivers Angela
Published: April 2019

Sickle cell disease (SCD) is an inheritable hemoglobinopathy characterized by polymerization of hemoglobin S in red blood cells resulting in chronic hemolytic anemia, vaso-occlusive painful crisis, and multiorgan damage. In SCD, an increased reactive oxygen species (ROS) generation occurs both inside the red blood cells and inside the vascular lumen, which augment hemolysis and cellular adhesion. This review discusses the evolving body of literature on the role of ROS in the pathophysiology of SCD as well as some emerging therapeutic approaches to SCD with a focus on the reduction of ROS.
Uncoding the genetic heterogeneity of myelodysplastic syndrome
Authors: Lindsley R. Coleman
Published: April 2019

Myelodysplastic syndrome (MDS) is a clinically heterogeneous disease characterized by functional impairment of hematopoiesis and abnormal bone marrow morphology. The type and severity of hematopoietic dysfunction in MDS are highly variable, and the kinetics of disease progression are difficult to predict. Genomic studies have shown that MDS is typically driven by a multistep somatic genetic process affecting a core set of genes. By definition, recurrent MDS driver mutations all drive clonal dominance, although they can have stereotyped positions in the clonal hierarchy or patterns of comutation association and exclusivity. Furthermore, environmental context, such as exposures to cytotoxic chemotherapy or the presence of germ-line predisposition, can influence disease pathogenesis and clinical outcomes. This review will address how an enhanced understanding of MDS genetics may enable refinement of current diagnostic schema, improve understanding of the pathogenesis of therapy-related MDS, and identify germ-line predispositions to development of MDS that are more common than recognized by standard clinical evaluation.
Current treatment algorithm for the management of lower-risk MDS
Authors: Giagounidis Aristoteles
Published: April 2019

Lower risk myelodysplastic syndromes (MDS), defined as MDS with a Revised International Prognostic Scoring System score ≤3.5 points, will remain a challenging entity in 2018. Supportive care continues to be the linchpin of treatment, although the options to reduce transfusion needs are broadening. To achieve red blood cell transfusion independence in non-del(5q) patients, erythropoiesis-stimulating agents remain a mainstay of therapy as long as endogenous erythropoietin levels are <500 U/L (and preferably <200 U/L). Experimental strategies for patients ineligible for erythropoiesis-stimulating agents or relapsing after gaining transfusion independence include immunosuppressive agents, transforming growth factor β inhibitors, and lenalidomide. All these alternatives have shown reasonable response rates in selected patient populations with lower risk MDS. Patients with del(5q) disease can derive long-term benefit from lenalidomide, and some patients remain transfusion free for extended periods even after discontinuation of the drug. In rare cases in which thrombocytopenia is the main clinical problem leading to clinically significant bleeding events, thrombopoietin receptor analogues may alleviate bleeding, increase platelet counts, and rarely lead to trilineage responses. It seems prudent to use these drugs only in patients with confirmed bone marrow blast counts <5%. Allogeneic stem cell transplantation is reasonable for patients with high molecular risk of progression and those failing several lines of treatment with signs of progression toward higher-risk MDS.
What are the current treatment approaches for patients with polycythemia vera and essential thrombocythemia?
Authors: Vannucchi Alessandro M. , Guglielmelli Paola
Published: April 2019

Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms that are characterized by thrombohemorrhagic complications, symptom burden, and impaired survival mainly due to thrombosis, progression to myelofibrosis, and transformation to acute leukemia. In this manuscript, we will review the most recent changes in diagnostic criteria, the improvements in risk stratification, and the “state of the art” in the daily management of these disorders. The role of conventional therapies and novel agents, interferon α and the JAK2 inhibitor ruxolitinib, is critically discussed based on the results of a few basic randomized clinical studies. Several unmet needs remain, above all, the lack of a curative approach that might overcome the still burdensome morbidity and mortality of these hematologic neoplasms, as well as the toxicities associated with therapeutic agents.
Management of multiple myeloma in the relapsed/refractory patient
Authors: Sonneveld Pieter
Published: April 2019

The approach to the patient with relapsed or relapsed/refractory multiple myeloma requires a careful evaluation of the results of previous treatments, the toxicities associated with it, and an assessment of prognostic factors. The majority of patients will have received prior therapy with drug combinations, including a proteasome inhibitor and an immune-modulatory agent. It is the physician’s task to choose the right moment for the start of therapy and decide with the patient which goals need to be achieved. The choice of regimen is usually based on prior response, drugs already received, adverse effects, comorbidities of the patient, and expected efficacy and tolerability. Many double and triple drug combinations are available. In addition, promising new drugs such as pomalidomide, carfilzomib, and monoclonal antibodies are or will be available shortly, and other options can be explored in clinical trials. Finally, supportive care and palliative options need to be considered in later relapsed disease. Increasingly, it becomes important to consider the therapeutic options for the whole duration of the disease and integrate a systematic approach for the patient.
Optimizing the care model for an uncomplicated acute pain episode in sickle cell disease
Authors: Telfer Paul , Kaya Banu
Published: April 2019

The pathophysiology, clinical presentation, and natural history of acute pain in sickle cell disease are unique and require a disease-centered approach that also applies general principles of acute and chronic pain management. The majority of acute pain episodes are managed at home without the need to access health care. The long-term consequences of poorly treated acute pain include chronic pain, adverse effects of chronic opioid usage, psychological maladjustment, poor quality of life, and excessive health care utilization. There is no standard protocol for management of an acute pain crisis in either the hospital or the community. The assumptions that severe acute pain must be managed in the hospital with parenteral opioids and that strong opioids are needed for home management of pain need to be questioned. Pain management in the emergency department often does not meet acceptable standards, while chronic use of strong opioids is likely to result in opioid-induced hyperalgesia, exacerbation of chronic pain symptoms, and opioid dependency. We suggest that an integrated approach is needed to control the underlying condition, modify psychological responses, optimize social support, and ensure that health care services provide safe, effective, and prompt treatment of acute pain and appropriate management of chronic pain. This integrated approach should begin at an early age and continue through the adolescent, transition, and adult phases of the care model.
Developing T-cell therapies for lymphoma without receptor engineering
Authors: Grant Melanie , Bollard Catherine M.
Published: April 2019

T-cell therapy has emerged from the bench for the treatment of patients with lymphoma. Responses to T-cell therapeutics are regulated by multiple factors, including the patient’s immune system status and disease stage. Outside of engineering of chimeric antigen receptors and artificial T-cell receptors, T-cell therapy can be mediated by ex vivo expansion of antigen-specific T cells targeting viral and/or nonviral tumor-associated antigens. These approaches are contributing to enhanced clinical responses and overall survival. In this review, we summarize the available T-cell therapeutics beyond receptor engineering for the treatment of patients with lymphoma.
Plasma exchange in thrombotic microangiopathies (TMAs) other than thrombotic thrombocytopenic purpura (TTP)
Authors: Winters Jeffrey L.
Published: April 2019

Thrombotic microangiopathies (TMAs) are a diverse group of disorders that are characterized by common clinical and laboratory features. The most commonly thought-of TMA is thrombotic thrombocytopenic purpura (TTP). Because of the marked improvement in patient mortality associated with the use of therapeutic plasma exchange (TPE) in TTP, this therapy has been applied to all of the TMAs. The issue, however, is that the pathophysiology varies and in many instances may represent a disorder of the endothelium and not the blood; in some cases, the pathophysiology is unknown. The use of TPE is further obscured by a lack of strong supporting literature on its use, with most consisting of case series and case reports; controlled or randomized controlled trials are lacking. Evidence supporting the use of TPE in the treatment of TMAs (other than TTP and TMA–complement mediated) is lacking, and therefore its role is uncertain. With the greater availability of genetic testing for mutations involving complement regulatory genes and complement pathway components, there seems to be a percentage of TMA cases, other than TMA–complement mediated, in which complement pathway mutations are involved in some patients. The ability of TPE to remove abnormal complement pathway components and replace them with normal components may support its use in some patients with TMAs other than TTP and TMA–complement mediated.
HLA donor-specific antibodies in allogeneic hematopoietic stem cell transplantation: challenges and opportunities
Authors: Gladstone Douglas E. , Bettinotti Maria P.
Published: April 2019

Allogenic hematopoietic stem cell recipients may have preformed antibodies directed against foreign HLA antigens. The use of partially HLA-mismatched allogeneic hematopoietic stem cell donors allows for the possibility of the presence of circulating HLA donor-specific antibodies (DSAs) in the recipient. The presence of DSAs at the time of stem cell infusion increases the risk of primary graft failure. More recently developed technology using solid phase immunoassays (SPIs) with fluorochrome-conjugated beads has greatly improved the ability to detect and classify DSAs. When used in combination with the classic lymphocytotoxic complement-dependent and flow cytometric crossmatch tests, SPIs help provide DSA strength assessment. Parous females frequently harbor DSAs. DSAs tend to be of higher intensity when directed against haploidentical first-degree relatives. DSA assessment requires frequent monitoring as their relative strength can change over time. Although the criteria that constitutes a prohibitive DSA is unknown, desensitization techniques can result in engraftment rates as experienced in fully HLA-matched allogeneic blood or marrow transplantation recipients.
Clinical implications of somatic mutations in aplastic anemia and myelodysplastic syndrome in genomic age
Authors: Maciejewski Jaroslaw P. , Balasubramanian Suresh K.
Published: April 2019

Recent technological advances in genomics have led to the discovery of new somatic mutations and have brought deeper insights into clonal diversity. This discovery has changed not only the understanding of disease mechanisms but also the diagnostics and clinical management of bone marrow failure. The clinical applications of genomics include enhancement of current prognostic schemas, prediction of sensitivity or refractoriness to treatments, and conceptualization and selective application of targeted therapies. However, beyond these traditional clinical aspects, complex hierarchical clonal architecture has been uncovered and linked to the current concepts of leukemogenesis and stem cell biology. Detection of clonal mutations, otherwise typical of myelodysplastic syndrome, in the course of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria has led to new pathogenic concepts in these conditions and created a new link between AA and its clonal complications, such as post-AA and paroxysmal nocturnal hemoglobinuria. Distinctions among founder vs subclonal mutations, types of clonal evolution (linear or branching), and biological features of individual mutations (sweeping, persistent, or vanishing) will allow for better predictions of the biologic impact they impart in individual cases. As clonal markers, mutations can be used for monitoring clonal dynamics of the stem cell compartment during physiologic aging, disease processes, and leukemic evolution.
HITs and misses in 100 years of heparin
Authors: Rice Lawrence
Published: April 2019

Heparin was discovered 100 years ago, and the heparin-induced thrombocytopenia syndrome was described 40 years ago. That the most powerful anticoagulant of the last century can also produce the most extreme prothrombotic diathesis is but one of the paradoxes that surround heparin-induced thrombocytopenia. Standard treatment is alternative anticoagulation. Advances continue to be made regarding pathophysiology, prevention, and treatment. Currently, an epidemic of overdiagnosis threatens the well-being of patients, so efforts to educate clinicians on when and how to make this diagnosis are pressing.
Thrombectomy and thrombolysis for the prevention and treatment of postthrombotic syndrome
Authors: Vedantham Suresh
Published: April 2019

Postthrombotic syndrome (PTS) is a frequent complication of lower-extremity deep vein thrombosis (DVT), occurring in approximately 40% of patients despite the use of anticoagulant therapy. PTS causes significant impairment of patients’ health-related quality of life, and no evidence-based therapies have been consistently effective. Catheter-directed thrombolysis and thrombectomy have been shown to remove acute thrombus, and it has been hypothesized they could prevent or reduce PTS. However, because these procedures can be associated with complications, mainly bleeding, randomized trial data are needed to determine when they should be used. In this article, I summarize the current status of thrombus removal procedures for DVT to provide contemporary guidance to clinicians seeking to individualize treatment decisions for their patients.
Inferior vena cava filter use and patient safety: legacy or science?
Authors: Geerts William , Selby Rita
Published: April 2019

There has been a dramatic increase in vena cava filter (VCF) use over the past 20 years in the absence of evidence that filters provide a net patient benefit or are required in most cases. This increase is largely attributable to the availability of retrievable filters and expanded indications, particularly as primary prophylaxis in patients thought to be at high risk of pulmonary embolism. Substantial variability in VCF use, unrelated to patient clinical factors, has been shown between hospitals, from region to region, and among various countries. Despite the lack of direct evidence for the benefit of VCFs for any indication, it is appropriate to insert a retrievable VCF in patients with a recent proximal deep vein thrombosis and an absolute contraindication to therapeutic anticoagulation and then to remove the filter once the bleeding risk decreases and the patient has been anticoagulated. Unfortunately, a high proportion of retrievable filters are not removed, even after the reason for their placement has long passed. Retrievable filters are associated with substantial rates of complications if they are not removed, including penetration of the vena caval wall, fracture and embolization of filter fragments, and caval occlusion. Patient safety priorities and medical-legal concerns mandate careful selection of patients for VCF placement and removal shortly after anticoagulation has been initiated.
Graft versus tumor effects and why people relapse
Authors: Falkenburg J. H. Frederik , Jedema Inge
Published: April 2019

Graft-versus-tumor (GVT) reactivity mediated by donor T cells in the context of allogeneic stem cell transplantation (alloSCT) is one of the most potent forms of cellular immunotherapy. The antitumor effect against hematologic malignancies is mediated by a polyclonal T-cell response targeting polymorphic antigens expressed on hematopoietic tissues of the recipient, leaving donor hematopoiesis in the patient after transplantation unharmed. Fortunately, hematopoietic tissues (including malignant hematopoietic cell populations) are relatively susceptible to T-cell recognition. If, however, nonhematopoietic tissues of the recipient are targeted as well, graft-versus-host disease (GVHD) will occur. The balance between GVT and GVHD is influenced by the genetic disparity between donor and recipient, the number and origin of professional antigen-presenting cells provoking the immune response, the target antigen specificity, magnitude and diversity of the response, and the in vivo inflammatory environment, whereas inhibitory factors may silence the immune response. Manipulation of each of these factors will determine the balance between GVT and GVHD.
Cells to prevent/treat relapse following allogeneic stem cell transplantation
Authors: Dietz Andrew C. , Wayne Alan S.
Published: April 2019

Relapse of cancer remains one of the primary causes of treatment failure and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). A multitude of approaches have been used in the management of posttransplant relapse. This review focuses on recent data with cellular therapies designed to treat or prevent posttransplant relapse of hematologic malignancies, although many of these therapeutic approaches also have applications to solid tumors and in the nontransplant setting. Currently available cell therapies include second transplant, natural killer cells, monocyte-derived dendritic cell vaccines, and lymphocytes via donor lymphocyte infusion, antigen-primed cytotoxic T lymphocytes, cytokine-induced killer cells, marrow-infiltrating lymphocytes, and chimeric antigen receptor T cells. These treatment options offer the prospect for improved relapse-free survival after HSCT.
Aging, hematopoiesis, and the myelodysplastic syndromes
Authors: Chung Stephen S. , Park Christopher Y.
Published: April 2019

The aging hematopoietic system undergoes numerous changes, including reduced production of red blood cells and lymphocytes as well as a relative increase in the production of myeloid cells. Emerging evidence indicates that many of these changes are due to selection pressures from cell-intrinsic and cell-extrinsic factors that result in clonal shifts in the hematopoietic stem cell (HSC) pool, resulting in predominant HSC clones that exhibit the functional characteristics associated with HSC aging. Given the recent descriptions of clonal hematopoiesis in aged populations, the increased risk of developing hematologic malignancies in individuals with clonal hematopoiesis, and the many similarities in hematopoietic aging and acquired bone marrow failure (BMF) syndromes, such as myelodysplastic syndromes (MDS), this raises significant questions regarding the relationship between aging hematopoiesis and MDS, including the factors that regulate HSC aging, whether clonal hematopoiesis is required for the development of MDS, and even whether BMF is an inevitable consequence of aging. In this article, we will review our current understanding of these processes and the potential intersections among them.
Managing myelofibrosis (MF) that “blasts” through: advancements in the treatment of relapsed/refractory and blast-phase MF
Authors: Scherber Robyn M. , Mesa Ruben A.
Published: April 2019

Myelofibrosis (MF) is the most aggressive form of Philadelphia chromosome–negative myeloproliferative neoplasm, and it is complicated by severe symptom burden, thrombotic events, infections, cytopenias, and transformation to acute myeloid leukemia (AML). Ruxolitinib, the first-line therapy for symptomatic or intermediate- and high–prognostic risk MF, has improved overall survival for this population. However, approximately one-half of MF patients will discontinue ruxolitinib by the first few years of therapy due to a spectrum of resistance, intolerance, relapse, or progression to blast phase disease. Danazol, erythropoietin-stimulating agents, and spleen-directed therapies can be useful in the ruxolitinib-resistant setting. In the ruxolitinib-refractory or -intolerant setting, commercial and novel therapies, either alone or in combination with ruxolitinib, have shown clinical utility. For blast-phase MF, the recent advancements in available AML therapies have increased the options with targeted and more tolerable therapies. In this article, we will discuss our paradigm for the management of relapsed/refractory and blast-phase MF in the context of therapeutic advancements in both AML and MF.
Adolescent angst: enrollment on clinical trials
Authors: Keegan Theresa H. M. , Parsons Helen M.
Published: April 2019

Survival among adolescents and young adults (AYAs) ages 15 to 39 with cancer has not improved to the same extent as that of pediatric and older adult cancer patients, which is thought to relate, in part, to the lower participation of AYAs in clinical trials. Because significant efforts have been made to improve clinical trial enrollment for AYAs, we (1) present contemporary clinical trial enrollment rates by cancer type, sociodemographic characteristics, and treatment setting and (2) discuss provider-, patient-, and system-level barriers to clinical trial participation. Contemporary studies examining clinical trial enrollment among AYAs have continued to find low overall participation relative to pediatric populations, with most studies observing no significant improvements in enrollment over time. In addition to age and cancer type, enrollment varies by treatment setting, health insurance, and race/ethnicity. Access to available clinical trials may be increased by appropriate referral of AYAs to pediatric and adult specialty cancer centers with studies relevant to the AYA population because most AYAs are treated in the community setting. Even with similar access to trials, however, AYAs may be less likely to participate, and therefore, future efforts should focus on better understanding and addressing barriers to enrollment as well as improving education and outreach regarding clinical trials.
The argument for using imatinib in CML
Authors: Claudiani Simone , Apperley Jane F.
Published: April 2019

June 2018 was the 20th anniversary of the clinical use of the first tyrosine kinase inhibitor (TKI), imatinib, for chronic myeloid leukemia. Since then, the change in prognosis for patients with this disease is one of the major success stories of modern cancer medicine. The dilemmas that face physicians and patients are no longer only those concerned with delaying inevitable progression to the terminal blastic phase or selecting the individuals most likely to benefit from allogeneic stem-cell transplantation; rather, they are now focused also on the choice of TKI, the management of comorbidities and adverse effects, strategies to improve quality of life, and the appropriateness of a trial of therapy discontinuation. Interestingly, with 4 TKIs approved for frontline use, the choice of initial therapy continues to cause controversy, a situation made more complicated by the tantalizing prospect of treatment-free remission. In this manuscript, we will explore the factors influencing this decision and try to provide a pragmatic and clinically applicable solution.
Sequencing of therapies in relapsed follicular lymphoma
Authors: Nastoupil Loretta J. , Flowers Christopher R. , Leonard John P.
Published: April 2019

Follicular lymphoma (FL) is an incurable but treatable disease with vast treatment options. Despite the abundance of efficacious treatment modalities, there is no universally agreed upon standard approach to treatment, particularly in the relapsed/refractory setting. There is an increasing need for more robust and clinically available tools to risk-stratify patients and identify those likely to experience early relapse, which is currently recognized as the unmet need in FL. Additionally, the use of gene-expression profiling and next-generation sequencing techniques in recent years has led to a wealth of knowledge regarding the molecular drivers of lymphomagenesis. However, much of this knowledge is not currently available in the clinic to inform treatment decisions. Future studies are needed to generate clinically relevant predictive models adept at incorporating patient-specific and molecular features to inform management strategies along the entire disease continuum as treatment decisions should not be made in a vacuum with a one-size-fits-all approach. Sequencing of therapy in the management of relapsed FL should involve personalized decision-making for care plans that balance patient characteristics, preferences, and comorbidities with treatment-related factors such as efficacy, toxicity profile, and mechanisms of action to achieve a durable, quality remission.
Richter transformation in the era of novel agents
Authors: Ding Wei
Published: April 2019

Recent approvals of several oral targeted agents have revolutionized chronic lymphocytic leukemia (CLL) therapy. However, CLL patients continue to progress; particularly, 4% to 20% of previously treated CLL patients undergo transformation into high-grade lymphoma. Richter transformation is defined as a transformation of CLL into aggressive lymphoma, most commonly diffuse large B-cell lymphoma. These patients typically have poor response to traditional chemotherapy used to treat de novo diffuse large B-cell lymphoma and similar or shorter overall survival (median 3-11 months) in the era of novel agents. Here, I review the contemporary literature on Richter transformation, particularly in the context of novel agents used in CLL, and discuss the management approach for these patients.
Role of the anticoagulant monitoring service in 2018: beyond warfarin
Authors: Clark Nathan P.
Published: April 2019

The direct oral anticoagulants (DOACs) have a wide therapeutic index, few drug interaction, no dietary interactions and do not require dose adjustment according to the results of routine coagulation testing. Despite these advantages over warfarin, the DOACs remain high risk medications. There is evidence that non-adherence, off-label dosing and inadequate care transitions during DOAC therapy increase the risk of bleeding and thromboembolic complications. Although DOACs are approved for a growing number of indications, there remain patient populations who are not good candidates. Existing expertise within an Anticoagulation Management Service (AMS) should be leveraged to optimize all anticoagulant therapies including the DOACs. The AMS can facilitate initial drug therapy selection and dose management, reinforce patient education and adherence as well as managing drug interactions and invasive procedures. In the event that a transition to warfarin is warranted, the AMS is already engaged which limits the risk of fragmented patient care and ensures that therapeutic anticoagulation is re-established in a timely manner. The AMS of the future will provide comprehensive management for all patients receiving anticoagulant medications and continue to provide anticoagulation expertise to the healthcare team.
Evaluation and management of heavy menstrual bleeding in adolescents: the role of the hematologist
Authors: O’Brien Sarah H.
Published: April 2019

Heavy menstrual bleeding (HMB) is frequently reported by adolescents. The role of the hematologist is threefold in evaluating such patients: (1) perform a clinical and laboratory evaluation for an underlying bleeding disorder on the basis of the degree of clinical suspicion, (2) identify and manage any concomitant iron deficiency, and (3) provide input to the referring provider regarding the management of HMB, particularly for patients with identified hemostatic defects. Several clues in the menstrual history should raise suspicion for an underlying bleeding disorder, such as menses lasting >7 days, menstrual flow which soaks >5 sanitary products per day or requires product change during the night, passage of large blood clots, or failure to respond to conventional therapies. A detailed personal and family history of other bleeding symptoms should also be obtained. Iron deficiency with and without anemia is commonly found in young women with HMB. Therefore, it is important to obtain measures of hemoglobin and ferritin levels when evaluating these patients. Iron supplementation is often a key component of management in the adolescent with heavy menses and is still needed in those who have received packed red cell transfusions as a result of severe anemia. Strategies for decreasing menstrual blood flow are similar for adults and adolescents with heavy menses, with combined hormonal contraceptives recommended as first-line therapy. However, there are adolescent-specific considerations for many of these agents, and they must be incorporated into shared decision-making when selecting the most appropriate treatment.
Elite athletes and anticoagulant therapy: an intermittent dosing strategy
Authors: Moll Stephan , Berkowitz Joshua N. , Miars Christopher W.
Published: April 2019

Traditionally, the athlete who requires long-term anticoagulation has been told to forgo participation in contact and collision sports. However, a strategy of short-term interruption of anticoagulant therapy may be designed for some athletes, allowing them return to full athletic activity. A personalized pharmacokinetic/pharmacodynamic study of a direct oral anticoagulant (DOAC) may allow athletic participation when plasma drug concentration is minimal and resumption of treatment after the risk of bleeding sufficiently normalizes. Scientific data and uncertainties regarding this approach, as well as practical challenges in the implementation, will be discussed.
Alternative donor transplants for severe aplastic anemia
Authors: Bacigalupo Andrea
Published: April 2019

Allogeneic hematopoietic stem-cell transplantation remains the only curative treatment for patients with acquired severe aplastic anemia (SAA). When a matched sibling is not available, one can search for a matched unrelated donor or a cord blood unit (CB) in the international registries or, more recently, for an HLA haploidentical (HAPLO) family member. International guidelines call for a course of antithymocyte globulin (ATG) and cyclosporine before a patient with SAA receives a transplant from a donor other than an HLA identical sibling, but whether this is necessary for patients age <20 years is less clear. Here I will examine the rapid increase in HAPLO transplantations for SAA, showing encouraging early results both in children and young adults. Graft-versus-host disease prophylaxis remains of primary importance in patients with SAA, and in vivo T-cell depletion with either ATG or alemtuzumab offers a significant survival advantage. Finally, I will discuss the strong age effect, which is particularly evident at >40 and 50 years of age for reasons not entirely clear and which should be taken into account when designing a treatment strategy for a given patient.
Measuring success: utility of biomarkers in sickle cell disease clinical trials and care
Authors: Kalpatthi Ram , Novelli Enrico M.
Published: April 2019

Progress in the care of sickle cell disease (SCD) has been hampered by the extreme complexity of the SCD phenotype despite its monogenic inheritance. While epidemiological studies have identified clinical biomarkers of disease severity, with a few exceptions, these have not been routinely incorporated in clinical care algorithms. Furthermore, existing biomarkers have been poorly apt at providing objective parameters to diagnose sickle cell crisis, the hallmark, acute complication of SCD. The repercussions of these diagnostic limitations are reflected in suboptimal care and scarcity of adequate outcome measures for clinical research. Recent progress in molecular and imaging diagnostics has heralded a new era of personalized medicine in SCD. Precision medicine strategies are particularly timely, since molecular therapeutics are finally on the horizon. This chapter will summarize the existing evidence and promising data on biomarkers for clinical care and research in SCD.
Adult and pediatric mechanical circulation: a guide for the hematologist
Authors: Kreuziger Lisa Baumann , Massicotte M. Patricia
Published: April 2019

Mechanical circulatory support (MCS) is the overarching term that encompasses the temporary and durable devices used in patients with severe heart failure. MCS disturbs the hematologic and coagulation system, leading to platelet activation, activation of the contact pathway of coagulation, and acquired von Willebrand syndrome. Ischemic stroke and major hemorrhage occur in up to 30% of patients. Hematologists are an essential part of the MCS team because they understand the delicate balance between bleeding and clotting and alteration of hemostasis with antithrombotic therapy. However, prior to this important collaborative role, learning the terminology used in the field and types of MCS devices allows improved communication with the MCS team and best patient care. Understanding which antithromobotic therapies are used at baseline is also required to provide recommendations if hemorrhage or thrombosis occurs. Additional challenging consultations in MCS patients include the influence of thrombophilia on the risk for thrombosis and management of heparin-induced thrombocytopenia. This narrative review will provide a foundation to understand MCS devices how to prevent, diagnose, and manage MCS thrombosis for the practicing hematologist.