Showing papers in "Hematology in 2017"
TL;DR: This chapter discusses the general approach to iron chelation therapy based on organ involvement using the available iron chelators: deferoxamine, deferiprone, and deferasirox.
Abstract: Thalassemic disorders lie on a phenotypic spectrum of clinical severity that depends on the severity of the globin gene mutation and coinheritance of other genetic determinants. Iron overload is associated with increased morbidity in both patients with transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). The predominant mechanisms driving the process of iron loading include increased iron burden secondary to transfusion therapy in TDT and enhanced intestinal absorption secondary to ineffective erythropoiesis and hepcidin suppression in NTDT. Different organs are affected differently by iron overload in TDT and NTDT owing to the underlying iron loading mechanism and rate of iron accumulation. Serum ferritin measurement and noninvasive imaging techniques are available to diagnose iron overload, quantify its extent in different organs, and monitor clinical response to therapy. This chapter discusses the general approach to iron chelation therapy based on organ involvement using the available iron chelators: deferoxamine, deferiprone, and deferasirox. Other novel experimental options for treatment and prevention of complications associated with iron overload in thalassemia are briefly discussed.
152 citations
TL;DR: The future of AL amyloidosis treatment is combination therapy and will require an innovative collaborative model for a rapid translation from bench to bedside with the ultimate aim of achieving a cure for this complex disease.
Abstract: Systemic amyloidosis is caused by misfolding and extracellular deposition of circulating proteins as amyloid fibrils, resulting in the dysfunction of vital organs. The most common systemic amyloidosis, light-chain (AL) amyloidosis, is caused by misfolded light chains produced by a small, dangerous B-cell clone. The process of amyloid formation, organ targeting, and damage is multifaceted and, after disease initiation, the complexity of the downstream pathogenic cascade increases, rendering its control a challenge. Because of the progressive nature of the disease, early diagnosis to prevent end-stage organ damage is vital. Improving awareness and systematic use of biomarkers of organ damage in screening populations at risk may improve the still unsatisfactory diagnostic process. Amyloid imaging is now emerging as an important companion of biomarkers in formulating the diagnosis and prognosis and monitoring the effects of therapy. An accurate diagnosis is the basis for appropriate therapy that is risk-adapted and response-tailored. Effective treatments targeting the clone and rapidly and profoundly reducing the amyloid light chains have produced marked improvements in overall survival, making AL amyloidosis the most successful model of all amyloidoses. New therapies targeting the amyloid deposits are now under development, together with novel agents modulating light chain aggregation and proteotoxicity. The future of AL amyloidosis treatment is combination therapy and will require an innovative collaborative model for a rapid translation from bench to bedside with the ultimate aim of achieving a cure for this complex disease.
124 citations
TL;DR: The objective of this research was to heighten awareness of Gaucher disease (GD), a rare lysosomal storage disorder with highly heterogeneous patterns of organ involvement and disease severity, to clinicians most likely to encounter these patients, and to summarize the published evidence on GD epidemiology to accurately depict the total societal burden of this rare worldwide disorder.
Abstract: Objectives: The objectives of this research were: (1) to heighten awareness of Gaucher disease (GD), a rare lysosomal storage disorder with highly heterogeneous patterns of organ involvement and disease severity, to clinicians most likely to encounter these patients, and; (2) to summarize the published evidence on GD epidemiology which is essential to accurately depict the total societal burden of this rare worldwide disorder.Methods: A comprehensive literature review was undertaken to summarize the published evidence on the epidemiology of GD. MEDLINE, EMBASE, CENTRAL, and ‘grey’ literature sources published in English between January 1990 and March 2015 were searched to identify relevant publications.Results: In total, 188 full-text articles were reviewed and findings from 49 studies are summarized herein. The standardized birth incidence of GD in the general population varied from 0.39 to 5.80 per 100 000, and prevalence ranged from 0.70 to 1.75 per 100 000, respectively. Time from onset of GD ...
101 citations
TL;DR: Although conventional clinical risk factors lose their independent prognostic significance when combined with MRD information, recently identified genetic markers may further improve the treatment stratification in ALL.
Abstract: Nowadays, minimal residual disease (MRD) is accepted as the strongest independent prognostic factor in acute lymphoblastic leukemia (ALL). It can be detected by molecular methods that use leukemia-specific or patient-specific molecular markers (fusion gene transcripts, or immunoglobulin/T-cell receptor [IG/TR] gene rearrangements), and by multi-parametric flow cytometry. The sensitivity and specificity of these methods can vary across treatment time points and therapeutic settings. Thus, knowledge of the principles and limitations of each technology is of the utmost importance for correct interpretation of MRD results. Time will tell whether new molecular and flow cytometric high-throughput technologies can overcome the limitations of current standard methods and eventually bring additional benefits. MRD during standard ALL chemotherapy is the strongest overall prognostic indicator and has therefore been used for refining initial treatment stratification. Moreover, MRD positivity after the maintenance phase of treatment may point to an impending relapse and thus enable salvage treatment to be initiated earlier, which could possibly improve treatment results. The prognostic relevance of pretransplantation MRD was shown by several studies, and MRD high-risk patients were shown to benefit from stem cell transplantation (SCT). Also, MRD positivity after SCT correlates with worse outcomes. In addition, MRD information is very instructive in current clinical trials that test novel agents to evaluate their treatment efficacy. Although conventional clinical risk factors lose their independent prognostic significance when combined with MRD information, recently identified genetic markers may further improve the treatment stratification in ALL.
98 citations
TL;DR: The introduction of high throughput sequencing (HTS) techniques greatly improved the knowledge of inherited thrombocytopenias (ITs) over the last few years, with specific attention focused on clinical presentations and diagnostic criteria for ITs predisposing to additional illnesses.
Abstract: 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.
89 citations
TL;DR: The optimal management of Acquired hemophilia A should be multidisciplinary and requires a close collaboration between physicians from various specialties.
Abstract: Objectives: Acquired hemophilia A (AHA) is a rare, but potentially life-threatening, bleeding disorder caused by an autoantibody against factor VIII that interferes with its coagulant function.Meth...
75 citations
TL;DR: The data suggest that the knockdown of HOTAIR may play a crucial role in improving acquired resistance to imatinib in CML K562-R cells via PI3K/Akt pathway.
Abstract: Objectives: Imatinib, a breakpoint cluster region-Abelson murine leukemia tyrosine kinase inhibitor, has revolutionized the treatment of chronic myelogenous leukemia (CML). However, the development of multidrug resistance (MDR) limits the clinical application of imatinib. In this study, we aimed to investigate the mechanisms of long noncoding RNA (lncRNA) HOTAIR in CML resistance to imatinib.Methods: Thirty-four CML patients were divided into multidrug resistance protein 1 (MRP1)-low and MRP1-high groups according to the median expression. Real-time PCR (qPCR) was used to detect the expression of lncRNA HOTAIR in CML patients, and MTT assay and flow cytometry assay were employed to detect the biological function of silencing lncRNA HOTAIR on the cell survival rate and apoptotic rate. An imatinib-resistant human CML cell line K562 (K562-R) was established, and western blot was used to detect the impact of lncRNA HOTAIR on the activation of PI3K/Akt signaling pathway.Results: Our results showed that...
68 citations
TL;DR: increasingly, it becomes important to consider the therapeutic options for the whole duration of the disease and integrate a systematic approach for the patient.
Abstract: 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.
63 citations
TL;DR: Clinical trials have shown that some patients with CML in the chronic phase who achieve sustained deep molecular responses on TKI therapy can safely suspend therapy with no evidence of relapse, and the concept of treatment-free remission should be considered as the future criterion to evaluate the success of clinical trials.
Abstract: Chronic myeloid leukemia (CML) is the best example of successful targeted therapy. Today, the overall survival of patients with CML treated by using tyrosine kinase inhibitors (TKIs) is very close to that of the healthy population. The current question is: how can we further ameliorate the clinical outcome of patients with CML? Clinical trials have shown that some patients with CML in the chronic phase who achieve sustained deep molecular responses on TKI therapy can safely suspend therapy with no evidence of relapse. The long follow-up studies and the number of eligible patients have now validated the concept of treatment-free remission (ie, the ability to maintain a molecular response after stopping therapy). It should be considered as the future criterion to evaluate the success of clinical trials, especially if we want to take into account the quality of life of patients in addition to the economic aspect. Because post-TKI discontinuation follow-ups have been increasing over time with no evidence of relapse in some patients, the next step for the coming decade will be to address the topic of CML cure.
63 citations
TL;DR: Progress in the treatment of patients with newly diagnosed multiple myeloma is summarized, addressing critical questions such as the optimal induction, early vs late ASCT, consolidation and/or maintenance for young patients, and how to choose the best treatment option for non-transplant-eligible patients.
Abstract: 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.
62 citations
TL;DR: 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 and assessment at the time of treatment requirement is recommended by most current guidelines for CLL management.
Abstract: 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.
TL;DR: From the clinical perspective, the development of thrombocytopenia in the ICU usually indicates serious organ system derangement and physiologic decompensation rather than a primary hematologic disorder.
Abstract: Thrombocytopenia is common among patients admitted to the intensive care unit (ICU). Multiple pathophysiological mechanisms may contribute, including thrombin-mediated platelet activation, dilution, hemophagocytosis, extracellular histones, ADAMTS13 deficiency, and complement activation. From the clinical perspective, the development of thrombocytopenia in the ICU usually indicates serious organ system derangement and physiologic decompensation rather than a primary hematologic disorder. Thrombocytopenia is associated with bleeding, transfusion, and adverse clinical outcomes including death, though few deaths are directly attributable to bleeding. The assessment of thrombocytopenia begins by looking back to the patient's medical history and presenting illness. This past information, combined with careful observation of the platelet trajectory in the context of the patient's clinical course, offers clues to the diagnosis and prognosis. Management is primarily directed at the underlying disorder and transfusion of platelets to prevent or treat clinical bleeding. Optimal platelet transfusion strategies are not defined, and a conservative approach is recommended.
TL;DR: This review will focus on the prior progress and current clinical trial investigation of rAAV-mediated gene transfer for hemophilia A and B.
Abstract: Concurrent with the development of recombinant factor replacement products, the characterization of the F9 and F8 genes over 3 decades ago allowed for the development of recombinant factor products and made the hemophilias a target disease for gene transfer. The progress of hemophilia gene therapy has been announced in 3 American Society of Hematology scientific plenary sessions, including the first “cure” in a large animal model of hemophilia B in 1998, first in human sustained vector-derived factor IX activity in 2011, and our clinical trial results reporting sustained vector-derived factor IX activity well into the mild or normal range in 2016. This progression to clinically meaningful success combined with numerous ongoing recombinant adeno-associated virus (rAAV)–mediated hemophilia gene transfer clinical trials suggest that the goal of gene therapy to alter the paradigm of hemophilia care may soon be realized. Although several novel therapeutics have recently emerged for hemophilia, gene therapy is unique in its potential for a one-time disease-altering, or even curative, treatment. This review will focus on the prior progress and current clinical trial investigation of rAAV-mediated gene transfer for hemophilia A and B.
TL;DR: A review of currently approved agents and promising novel agents in development and will highlight controversial areas in targeted treatment in acute myeloid leukemia.
Abstract: 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.
TL;DR: New formulations of intravenous iron with carbohydrate cores, which bind elemental iron more tightly, minimize the release of labile free iron to allow complete replacement doses of intravenOUS iron in 15 to 60 minutes, facilitating and simplifying care.
Abstract: Iron deficiency is the commonest cause of anemia during pregnancy; however, its prevalence is highly determined by nutritional and socioeconomic status. Oral iron is the frontline therapy, but is often poorly tolerated. Awareness of the available intravenous formulations is essential for management. Before delivery, risk factors such as multiparity and heavy uterine bleeding increase the prevalence of iron deficiency and should be motivation for early diagnosis and treatment. Neonates born with iron deficiency have a statistically significant increment in both cognitive and behavioral abnormalities that persist after repletion, highlighting the need for heightened awareness of the diagnosis. A smartphone application providing information on nutrition and treatment is provided. New formulations of intravenous iron with carbohydrate cores, which bind elemental iron more tightly, minimize the release of labile free iron to allow complete replacement doses of intravenous iron in 15 to 60 minutes, facilitating and simplifying care.
TL;DR: Non-chemotherapy idiosyncratic drug-induced neutropenia (IDIN) is a relatively rare but potentially fatal disorder that occurs in susceptible individuals, with an incidence of 2 to 15.4 cases per million population.
Abstract: Non-chemotherapy idiosyncratic drug-induced neutropenia (IDIN) is a relatively rare but potentially fatal disorder that occurs in susceptible individuals, with an incidence of 2.4 to 15.4 cases per million population. Affected patients typically experience severe neutropenia within several weeks to several months after first exposure to a drug, and mortality is ∼5%. The drugs most frequently associated with IDIN include metamizole, clozapine, sulfasalazine, thiamazole, carbimazole, amoxicillin, cotrimoxazole, ticlopidine, and valganciclovir. The idiosyncratic nature of IDIN, the lack of mouse models and diagnostic testing, and its low overall incidence make rigorous studies to elucidate possible mechanisms exceptionally difficult. An immune mechanism for IDIN involving neutrophil destruction by hapten (drug)-specific antibodies and drug-induced autoantibodies is frequently suggested, but strong supporting evidence is lacking. Although laboratory testing for neutrophil drug-dependent antibodies is rarely performed because of the complexity and low sensitivity of tests currently in use, these assays could possibly be enhanced by using reactive drug metabolites in place of the parent drug. Patients typically experience acute, severe neutropenia, or agranulocytosis (<0.5 × 109 neutrophils/L) and symptoms of fever, chills, sore throat, and muscle and joint pain. Diagnosis can be difficult, but timely recognition is critical because if left untreated, there is an increase in mortality. Expanded studies of the production and mechanistic role of reactive drug metabolites, genetic associations, and improved animal models of IDIN are essential to further our understanding of this important disorder.
TL;DR: The composite molecular architecture in acute myeloid leukemia has been mapped out and a clearer understanding of the key genetic determinants, the major genetic interactions, and the broad order in which these mutations occur is understood.
Abstract: 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.
TL;DR: 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.
Abstract: 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.
TL;DR: Preliminary evidence suggests that anticoagulation treatment may be beneficial for cancer patients with incidental distal deep vein thrombosis or incidental splanchnic vein thROMbosis.
Abstract: 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.
TL;DR: The introduction of computed tomographic pulmonary angiography and its recent increasing availability has led to a significant rise in its use to help clinicians diagnose acute pulmonary embolism, suggesting that a subgroup of patients with SSPE might be safely managed without the use of anticoagulant therapy.
Abstract: The introduction of computed tomographic pulmonary angiography and its recent increasing availability has led to a significant rise in its use to help clinicians diagnose acute pulmonary embolism (PE). This has led to a significant increase in the incidence of PE diagnoses. Simultaneously, the case fatality rate of acute PE has been decreasing and no significant change in its mortality has been noted, suggesting that the additional PE diagnoses are less severe and these patients might not benefit from anticoagulation therapy. This also seems to be correlated with an increase in the diagnosis of PE localized in the subsegmental pulmonary arteries (subsegmental pulmonary embolism [SSPE]). The clinical importance of SSPE is unclear. Whereas some studies have shown that it might be reasonable to manage patients with SSPE without anticoagulation, others have not. Although the current medical literature is limited, it suggests that a subgroup of patients with SSPE might be safely managed without the use of anticoagulant therapy. Current clinical practice guidelines suggest that clinicians take an individualized approach after carefully assessing the risk/benefit ratio for patients with SSPE and negative leg limb ultrasonography results. Prospective studies are ongoing and results are eagerly awaited to help tailor the management of this patient population.
TL;DR: A better understanding of the immunomodulatory effects of each ITP therapy is needed to best manage the disease.
Abstract: Objectives: Classically, immune thrombocytopenia (ITP) was thought to be caused by the destruction and insufficient production of platelets, as mediated by autoantibodies. More recently other immune mechanisms that contribute to the disease have been discovered. This review attempts to address the main unresolved questions in ITP.Methods: We review the most current knowledge of the pathophysiology of ITP. Immunological effects of available therapies are also described.Discussion: The trigger may be a loss of tolerance due to molecular mimicry with cross-reaction of antibodies arising from infectious agents or drugs, genetic factors, and/or platelet Toll receptors. This loss of tolerance activates autoreactive effector B and T lymphocytes, which in turn initiates platelet destruction, mediated by cytotoxic T lymphocytes and the release of pro-inflammatory cytokines (IL-2/IL-17) by T helper (Th) cells (Th1/Th17). Th2 (anti-inflammatory) and regulatory B (Breg) and Treg cells are also inhibited (with...
TL;DR: The research showed that the treatment of P-GEMOX combined with RT was a tolerable and effective treatment for localized nasal natural killer/T-cell lymphoma.
Abstract: Purpose: Extranodal natural killer/T-cell lymphoma (ENKTL), nasal-type, is a distinct subtype of non-Hodgkin lymphoma. ENKTL is sensitive to radiotherapy, but the prognosis is poorer than t...
TL;DR: Whole-brain irradiation and high-dose chemotherapy supported by autologous stem cell transplantation are 2 effective consolidation strategies in patients with a disease responsive to induction chemotherapy, and the pros and cons of these approaches together with the best candidates for each therapy are outlined.
Abstract: Primary central nervous system (CNS) lymphomas represent a subgroup of malignancies with specific characteristics, an aggressive course, and unsatisfactory outcome in contrast with other lymphomas comparable for tumor burden and histological type. Despite the high sensitivity to conventional chemotherapy and radiotherapy, remissions are frequently short lasting. Treatment efficacy is limited by several factors, including the biology and microenvironment of this malignancy and the "protective" effect of the blood-brain barrier, which limits the access of most drugs to the CNS. Patients who survive are at high risk of developing treatment-related toxicity, mainly disabling neurotoxicity, raising the question of how to balance therapy intensification with the control of side effects. Recent therapeutic progress and effective international cooperation have resulted in a significantly improved outcome over the past 2 decades, with a higher proportion of patients receiving treatment with curative intent. Actual front-line therapy consists of high-dose methotrexate-based polychemotherapy. Evidence supporting the addition of an alkylating agent and rituximab is growing, and a recent randomized trial demonstrated that the combination of methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) is associated with a significantly better overall survival. Whole-brain irradiation and high-dose chemotherapy supported by autologous stem cell transplantation are 2 effective consolidation strategies in patients with a disease responsive to induction chemotherapy. Different strategies such as alkylating maintenance, conservative radiotherapy, and nonmyeloablative consolidation are being addressed in large randomized trials and a more accurate knowledge of the molecular and biological characteristics of this malignancy are leading to the development of target therapies in refractory/relapsing patients, with the overall aim to incorporate new active agents as part of first-line treatment. The pros and cons of these approaches together with the best candidates for each therapy are outlined in this article.
TL;DR: Recommendations are made that optimal patient CV risk assessment needs to become a more central tenet of patient care in CML, especially those on chronic TKI therapy.
Abstract: Cardiovascular (CV) health has emerged as an important consideration in patients with chronic myeloid leukemia (CML) because of improved prognosis. Indeed, the success of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has increased the focus on survivorship and late toxicity in oncological care. Survivorship issues in this population include CV disease prevention, given its prevalence in the general population. The introduction of BCR-ABL1 TKIs represented a unique concept of indefinite cancer therapy, only recently evolving to include "treatment-free remission." Importantly, later-generation BCR-ABL1 TKIs have been associated with CV complications. Dasatinib has been associated with pleural/pericardial effusions and pulmonary hypertension, whereas nilotinib and ponatinib have been linked to the development of vascular occlusive events. There is currently a dearth of data with respect to the mechanisms of drug toxicities, the subsets of patients at risk, and prevention and treatment strategies to mitigate CV complications in patients with CML. Nevertheless, optimal patient CV risk assessment needs to become a more central tenet of patient care in CML. We propose several practical considerations for the practicing oncologist relative to the CV health of patients with CML, especially those on chronic TKI therapy.
TL;DR: Improvements in the design and manufacture of these devices, as well as in the individualized titration of antithrombotic intensity, are expected to enhance outcomes.
Abstract: 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.
TL;DR: 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 thROMbocy topenia, and coincident clinical and laboratory manifestations, and to provide guidance for dealing with some of the more common and difficult diagnostic and management decisions.
Abstract: 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.
TL;DR: Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.
Abstract: Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.
TL;DR: This is the first study of its kind conducted in Indonesia, which supports the fact that T2* MRI is undoubtedly valuable in the early detection of cardiac and hepatic iron overload in thalassemia major patients.
Abstract: Objectives: Recent advancements have promoted the use of T2* magnetic resonance imaging (MRI) in the non-invasive detection of iron overload in various organs for thalassemia major patients. This study aims to determine the iron load in the heart and liver of patients with thalassemia major using T2* MRI and to evaluate its correlation with serum ferritin level and iron chelation therapy.Methods: This cross-sectional study included 162 subjects diagnosed with thalassemia major, who were classified into acceptable, mild, moderate, or severe cardiac and hepatic iron overload following their T2* MRI results, respectively, and these were correlated to their serum ferritin levels and iron chelation therapy.Results: The study found that 85.2% of the subjects had normal cardiac iron stores. In contrast, 70.4% of the subjects had severe liver iron overload. A significant but weak correlation (r = −0.28) was found between cardiac T2* MRI and serum ferritin, and a slightly more significant correlation (r = ...
TL;DR: 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.
Abstract: 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.
TL;DR: Optimizing the risk-benefit ratio of treatment by decreasing toxicity whenever possible is the major goal of clinical research in this disease.
Abstract: 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.