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  • BITES and CARS and checkpoints, oh my! Updates regarding immunotherapy for myeloid malignancies from the 2018 annual ASH meeting
    Blood Rev. (IF 6.125) Pub Date : 2020-01-21
    Amanda C. Przespolewski; Elizabeth A. Griffiths

    It is without question that immune checkpoint inhibitors and adoptive cellular therapies have revolutionized the treatment of solid and hematologic malignancies. Investigators are now developing novel strategies to integrate these groundbreaking modalities into the care of patients with acute myeloid leukemia (AML) and other myeloid malignancies. Here we provide an overview of the most recent developments in immunotherapy for myeloid cancers presented at the 2018 American Society of Hematology annual meeting. Topics discussed include adoptive cellular therapies (CAR-T, NK cell, and vaccines), checkpoint inhibitors, and bispecific T-cell engager (BITE) antibodies. Despite reservations regarding low antigenicity and having long been considered a “cold” tumor, immunotherapy remains a highly promising strategy for patients with aggressive myeloid cancers like myelodysplasia (MDS) and AML.

  • Peripheral Neuropathy in Hematologic Malignancies – Past, Present and Future
    Blood Rev. (IF 6.125) Pub Date : 2020-01-17
    Tiffany Li; Hannah C. Timmins; Hillard M. Lazarus; Susanna B. Park

    Neurotoxic treatments (including proteasome inhibitors, immunomodulatory drugs and vinca-alkaloids) are often used in the treatment of hematologic malignancy. Peripheral neuropathy can be part of a paraneoplastic syndrome accompanying the disease but more commonly is a consequence of treatment with neurotoxic therapies, and produces sensory, motor, autonomic nerve dysfunction or a combination, leading to pain, loss of sensation and functional disability. This review provides an update on peripheral neuropathy in hematologic malignancy, including risk factors, mechanisms and treatment options. We examine the clinical features and risk factors for peripheral neuropathy following bortezomib, thalidomide, brentuximab vedotin and vinca alkaloid treatment, as well as related compounds. We review the current data on pharmacogenetic risk factors for the development of toxicity and highlight areas of future research.

  • After 95 years, it's time to eRASe JMML
    Blood Rev. (IF 6.125) Pub Date : 2020-01-16
    Sonia Meynier; Frédéric Rieux-Laucat

    Juvenile myelomonocytic leukaemia (JMML) is a rare clonal disorder of early childhood. Constitutive activation of the RAS pathway is the initial event in JMML. Around 90% of patients diagnosed with JMML carry a mutation in the PTPN11, NRAS, KRAS, NF1 or CBL genes. It has been demonstrated that after this first genetic event, an additional somatic mutation or epigenetic modification is involved in disease progression. The available genetic and clinical data have enabled researchers to establish relationships between JMML and several clinical conditions, including Noonan syndrome, Ras-associated lymphoproliferative disease, and Moyamoya disease. Despite scientific progress and the development of more effective treatments, JMML is still a deadly disease: the 5-year survival rate is ~50%. Here, we report on recent research having led to a better understanding of the genetic and molecular mechanisms involved in JMML.

  • Critical overview of the main features and techniques used for the evaluation of the clinical applicability of L-asparaginase as a biopharmaceutical to treat blood cancer
    Blood Rev. (IF 6.125) Pub Date : 2020-01-13
    T.A. Costa-Silva; I.M. Costa; H. Biasoto; G.M. Lima; C. Silva; A. Pessoa; G. Monteiro

    L-asparaginase is an enzyme used as a biopharmaceutical to treat acute lymphoblastic leukemia. Several adverse effects have been related to L-asparaginase use, so the scientific community has searched for novel proteoforms of L-ASNase. However, some critical characteristics must be considered for a novel L-ASNase source to be effective as an antitumour drug. Accordingly, this article provides a critical analysis of the parameters and methods applied to estimate L-ASNase concentration, measure the L-ASNase and GLNase activities and kinetics, evaluate the enzyme preparations purity and define the antitumour activity against leukemic cells in vitro. Among the main features, the proposed new enzyme needs to present high affinity for L-asparagine; low percentage of glutaminase activity in relation to L-ASNase; high enzyme stability and half-life and mainly antileukemic activity when a low protein amount is applied. These parameters are discussed in an attempt to guide the consideration of an enzyme as a promising biopharmaceutical against ALL.

  • The minimal that kills: Why defining and targeting measurable residual disease is the “Sine Qua Non” for further progress in management of acute myeloid leukemia
    Blood Rev. (IF 6.125) Pub Date : 2019-12-20
    Jan Philipp Bewersdorf; Rory M. Shallis; Prajwal C. Boddu; Brent Wood; Jerald Radich; Stephanie Halene; Amer M. Zeidan

    Patients with acute myeloid leukemia (AML) who achieve morphologic remission in the bone marrow after initial treatment often continue to harbor residual leukemic cells that can give rise to disease relapse. Achievement of a deeper remission has been associated with a reduced risk of relapse and improved event-free and overall survival in several studies. However, standardization of diagnostic techniques, sample acquisition and test timing are needed before minimal, also known as measurable, residual disease (MRD) quantification can be used to guide treatment decision making. Furthermore, clinical trial evidence that preemptive intervention at MRD level can alter the natural history of AML is required. Herein, we outline the current landscape of MRD assessment in AML, summarize the available evidence and challenges, and highlight the potential for MRD status to serve as a surrogate endpoint for hard clinical outcomes and as an approvable endpoint in clinical trials for regulatory purposes.

  • Impact of transfusion on survival in patients with myelodysplastic syndromes: Current knowledge, new insights and transfusion clinical practice
    Blood Rev. (IF 6.125) Pub Date : 2019-12-18
    Eléonore Kaphan; David Laurin; Bruno Lafeuillade; Philippe Drillat; Sophie Park

    Red Blood Cell (RBC) transfusion dependence is a prevalent consequence of anaemia in patients with lower risk Myelodysplastic Syndromes (MDS). These patients have shorter survival compared to patients responding to Erythropoiesis-stimulating agents (ESA), raising the question of potential negative effects of chronic RBC transfusions on MDS prognosis, independently of IPSS-R. Besides commonly identified complications of transfusions like iron toxicity or cardiac events, oxidative stress could be a risk factor for ineffective haematopoiesis. Recently, physicochemical changes of RBC during storage have been described. These changes called storage lesions could play a role in immunomodulation in vivo. We review the currently identified sources of potential impact on transfusion-associated effects in MDS patients and we discuss the unexplored potential role of erythrocyte-derived-extracellular vesicles. They could amplify impairment of haematopoiesis in addition to the negative intrinsic effects underlying the pathology in MDS. Thus, chronic RBC transfusions appear to potentially impact the outcome of MDS.

  • Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting
    Blood Rev. (IF 6.125) Pub Date : 2019-12-05
    Ulrich Jäger, Wilma Barcellini, Catherine M. Broome, Morie A. Gertz, Anita Hill, Quentin A. Hill, Bernd Jilma, David J. Kuter, Marc Michel, Marco Montillo, Alexander Röth, Sacha S. Zeerleder, Sigbjørn Berentsen

    Autoimmune hemolytic anemias (AIHAs) are rare and heterogeneous disorders characterized by the destruction of red blood cells through warm or cold antibodies. There is currently no licensed treatment for AIHA. Due to the paucity of clinical trials, recommendations on diagnosis and therapy have often been based on expert opinions and some national guidelines. Here we report the recommendations of the First International Consensus Group, who met with the aim to review currently available data and to provide standardized diagnostic criteria and therapeutic approaches as well as an overview of novel therapies. Exact diagnostic workup is important because symptoms, course of disease, and therapeutic management relate to the type of antibody involved. Monospecific direct antiglobulin test is considered mandatory in the diagnostic workup, and any causes of secondary AIHA have to be diagnosed. Corticosteroids remain first-line therapy for warm-AIHA, while the addition of rituximab should be considered early in severe cases and if no prompt response to steroids is achieved. Rituximab with or without bendamustine should be used in the first line for patients with cold agglutinin disease requiring therapy. We identified a need to establish an international AIHA network. Future recommendations should be based on prospective clinical trials whenever possible.

  • Tapering and discontinuation of thrombopoietin receptor agonists in immune thrombocytopenia: Real-world recommendations
    Blood Rev. (IF 6.125) Pub Date : 2019-11-30
    F. Zaja, M. Carpenedo, C. Baratè, A. Borchiellini, F. Chiurazzi, G. Finazzi, A. Lucchesi, F. Palandri, A. Ricco, C. Santoro, P.R. Scalzulli

    Thrombopoietin receptor agonists (TPO-RAs) are currently indicated for continuous treatment of chronic primary immune thrombocytopenia (ITP). However, there is growing evidence that TPO-RAs can also trigger sustained response in 10–30% of cases after treatment tapering and discontinuation. Therefore, at least for selected responding patients, it might be rational to plan TPO-RA interruption to exploit off-treatment response. Intriguingly, complete or partial responses with TPO-RAs are frequently observed when treatments are initiated early, suggesting that unknown immune-related mechanisms may be involved in this phenomenon. The sustained responses observed after interruption of TPO-RAs may be interpreted as a recovery of immunological tolerance; thus, the re-establishment of immunological equilibrium might be primarily responsible for the observed off-treatment effect. Importantly, these findings may indicate that anticipated TPO-RA usage can lead to improved responses, and that optimized tapering and interruption in selected patients can furthermore improve prognoses. On the base of this rationale, a series of real-life considerations have been generated by a panel of Experts to elucidate possible novel criteria and modalities to identify subgroups of patients who can benefit from tapering and/or discontinuation of TPO-RAs. Towards this aim, the results of a survey of ITP experts are herein reported, reflecting a snapshot of current real-life experience on early discontinuation of TPO-RA-based therapy. The present manuscript also highlights the importance of future translational studies on novel prognostic and predictive biomarkers that can stratify patients and facilitate the clinical choice for second-line treatment of ITP.

  • Why do myeloma patients have bone disease? A historical perspective
    Blood Rev. (IF 6.125) Pub Date : 2019-11-29
    Magne Børset, Anders Sundan, Anders Waage, Therese Standal

    The question of how myeloma cells cause destruction of skeletal tissue has interested scientists for many years, and knowledge in this field has developed in parallel with the understanding of physiological bone remodeling. The identification of bioactive proteins of the cytokine class during the last decades of the previous century and mapping of their role in the regulation of anabolic and catabolic processes in bone, led to a sequence of hypotheses about how the same peptides also could be involved in myeloma-driven bone destruction. Although bone remodeling is now understood in detail, there is still no clear unified theory of how myeloma cells degrade bone. The reason for this could be that there is no single mechanism that is active in every patient. The common trait is possibly that myeloma cells benefit from bone destruction per se, and the strategy they use to accomplish this vary between patients.

  • Autoimmunity as a target for chimeric immune receptor therapy: A new vision to therapeutic potential
    Blood Rev. (IF 6.125) Pub Date : 2019-11-28
    Mohammad-Hossein Haddadi, Ensiyeh Hajizadeh-Saffar, Mohsen Khosravi-Maharlooei, Mohsen Basiri, Babak Negahdari, Hossein Baharvand

    Chimeric immune receptors (CIRs) are functionally pleiotropic because they are artificially expressed on diverse cell types, which gives specificity to their function to anergize, kill, or protect cognate target cells. CIRs consist of chimeric antigen receptors (CARs) and B-cell antibody receptor (BAR) or chimeric autoantibody receptors (CAARs). Approval of CAR-T cell therapy by the Food and Drug Administration (FDA) has encouraged investigators to search for autoimmune therapies that are CIR-based. Both T effector cells, particularly CD8+, and T CD4+ regulatory cells (Tregs) can be engineered through CIR expression. Recently, natural killer cells have been included to increase efficiency. Unwanted antibody producer B cells are effectively prevented by CAAR-T cells, B-cell antibody receptor (BAR)-T CD8+, and BAR-Treg, which represents an advantage in antibody-mediated diseases such as pemphigus vulgaris (PV) and hemophilia A. Although CAAR and BAR-T cells may have curative benefits for autoantibody-mediated immune diseases, verification of long-term efficacy and safety are a priority before clinical use. Effective CIR-T cell therapy largely depends on the reliability and stability of the receptor. Based on CIR functionality, factors that explicitly determine effectiveness of the treatment should be considered. These factors include antigen/autoantibody specificity, single chain variable fragment (scFv) affinity, and autoantibody masking. Herein, we review the current evidence of CIR therapy with a focus on their therapeutic potential for autoimmune diseases and their challenges.

  • The emerging role of red blood cells in cytokine signalling and modulating immune cells
    Blood Rev. (IF 6.125) Pub Date : 2019-11-27
    Elisabeth Karsten, Benjamin R. Herbert

    For many years red blood cells have been described as inert bystanders rather than participants in intercellular signalling, immune function, or inflammatory processes. However, studies are now reporting that red blood cells from healthy individuals regulate immune cell activity and maturation, and red blood cells from disease cohorts are dysfunctional. These cells have now been shown to bind more than 50 cytokines and have been described as a sink for these molecules, and the loss of this activity has been correlated with disease progression. In this review, we summarise what is currently understood about the role of red blood cells in cytokine signalling and in modulating the activity of immune cells. We also discuss the implications of these findings for transfusion medicine and in furthering our understanding of anaemia of chronic inflammation. By bringing these disparate units of work together, we aim to shine a light on an area that requires significantly more investigation.

  • The evolving role of translocation t(11;14) in the biology, prognosis, and management of multiple myeloma
    Blood Rev. (IF 6.125) Pub Date : 2019-11-23
    Agne Paner, Pritesh Patel, Binod Dhakal

    Cytogenetic changes in multiple myeloma (MM) have emerged as one of the most important prognostic factors. Translocations of chromosomes 4 and 14 [t(4;14)], chromosomes 14 and 16 [t(14;16)] and deletion of chromosome 17p [del(17p)] have been incorporated in the Revised International Staging System as a measure of adverse disease biology. Ongoing research is unveiling a complex genomic landscape in MM, with new cytogenetic abnormalities important for prognosis identified and the significance of known cytogenetic changes revisited. In studies conducted before the novel agent era, t(11;14) was shown to carry standard risk for patients with MM. Findings from more recent retrospective reviews have shown that t(11;14) is associated with intermediate outcomes in patients treated with novel agents as compared with patients who have standard- or high-risk cytogenetic aberrations. MM cells with t(11;14) have a unique biology, with relatively higher expression of the proapoptotic protein BCL2 and lower expression of MCL1, in contrast to MM cells without this translocation. Translocation t(11;14) has emerged as the first predictive marker in MM, indicating susceptibility to BCL2 inhibition. Future studies will be needed to explore if the combination of novel agents with BCL2 inhibitors can improve the prognosis of patients with t(11;14). In this article, current data on the evolving role of t(11;14) in the biology, prognosis, and treatment of MM are reviewed.

  • Serological biomarkers in hemophilic arthropathy: Can they be used to monitor bleeding and ongoing progression of blood-induced joint disease in patients with hemophilia?
    Blood Rev. (IF 6.125) Pub Date : 2019-11-20
    E. Carlos Rodriguez-Merchan

    In patients with hemophilia, levels of uCTX-II and sCS846 increase 5 days after joint hemorrhage with respect to the initial value. In other words, in patients with established hemophilic arthropathy, the aforesaid biomarker of joint tissue damage augments shortly after the first joint hemorrhage. In patients with hemophilia treated on demand, a correlation has been found between magnetic resonance imaging scores and the CS846 biomarker. Patients with hemophilia having more than one joint with advanced arthropathy have shown high levels of circulating soluble vascular cell adhesion molecule-1 (sVCAM-1). In addition, VCAM-1 levels in these patients are associated with the severity of hemophilic arthropathy. In patients with hemophilia, cartilage degradation is increased by 25% compared with controls, as measured by some biomarkers (C2M, CTX-II and COMP). Levels of the cartilage degradation enzyme, ADAMTS5, are 10% lower in patients with hemophilia. Bone formation (PINP) is 25% lower in patients with hemophilia, whereas bone resorption (CTXI) is 30% greater. Acute inflammation (hsCRP) is 50% greater, whereas chronic inflammation (CRPM) is 25% lower. The hsCRP/CRPM ratio is 60% higher in patients with hemophilia than in controls. A panel of biomarkers that combines C2M, CRPM and ADAMTS5 can distinguish patients with hemophilia from controls with 85.3% accuracy. No strong correlation between biomarkers and the radiological and physical examination of the joint has been found.

  • Evolution of replacement therapy for von Willebrand disease: From plasma fraction to recombinant von Willebrand factor
    Blood Rev. (IF 6.125) Pub Date : 2019-04-03
    Flora Peyvandi, Peter Kouides, Peter L. Turecek, Edward Dow, Erik Berntorp

    The diagnosis and treatment of von Willebrand disease (VWD) are challenging, in part because patients exhibit a wide range of bleeding patterns and manifestations (e.g. epistaxis, gingival bleeding, heavy menstrual bleeding, gastrointestinal bleeds, postoperative bleeding, hemarthroses) and in part because many tests are required to make an accurate diagnosis. Factor replacement therapies for VWD are the mainstay of treatment for patients who do not respond to desmopressin. They have gradually evolved from crude preparations of plasma proteins to plasma-derived concentrates containing both von Willebrand factor (VWF) and factor VIII (FVIII). However, varying amounts and quality of VWF and varying content of FVIII have contributed to the lack of a standardized approach to replacement therapy. More recently, the treatment of VWD has undergone a slow yet significant change from plasma-derived VWF/FVIII concentrates with VWF:ristocetin cofactor (RCo)/FVIII ratios ≤1, to those with VWF:RCo/FVIII ratios >10, to a recombinant VWF. This article reviews the evolution of factor replacement therapy for patients with VWD that has occurred over the last several decades. The availability of a greater variety of factor replacement therapies poses a challenge in terms of a standard algorithm of care but may help overcome the limitations of earlier treatments and allow treatment personalization according to individual patient needs.

  • The central role of thrombin in bleeding disorders
    Blood Rev. (IF 6.125) Pub Date : 2019-05-22
    Claude Negrier, Midori Shima, Maureane Hoffman

    Maintaining normal hemostasis relies on a regulated system of procoagulant and anticoagulant pathways, and disruption of these processes leads to the loss of hemostatic control, with the potential for excessive bleeding or thrombosis. Evaluation of bleeding disorders has conventionally been achieved by laboratory assays that measure the activity of individual coagulation factors. While such assays have proven effective for detecting abnormalities of the coagulation system and aiding diagnosis, inherent limitations prevent them from capturing a complete picture of hemostatic function. An improved understanding of thrombin activity and its central role in hemostasis and bleeding disorders has led to the clinical development of global assays that are more physiologically relevant than traditional assays; furthermore, these global assays are able to monitor responses to therapy. In this review, we provide an overview of the role of thrombin in hemostasis, and describe the clinical benefits of thrombin monitoring in patients with bleeding disorders. Moreover, we discuss recent advances in thrombin-targeting therapeutic strategies that aim to correct thrombin deficiency and prevent bleeding in patients with hemophilia and other rare bleeding disorders.

  • Targeting steroid resistance in T-cell acute lymphoblastic leukemia
    Blood Rev. (IF 6.125) Pub Date : 2019-07-19
    Renate De Smedt, Julie Morscio, Steven Goossens, Pieter Van Vlierberghe

    T-cell acute lymphoblastic leukemia (T-ALL) is characterized by a variable response to steroids during induction and/or consolidation therapy. Notably, recent work suggested that these differences in glucocorticoid sensitivity might, at least in part, be mediated by hyperactivation of specific oncogenic pathways such as RAS/MEK/ERK, PI3K/AKT and IL7R/JAK/STAT. In this review, we elaborate on putative associations between aberrant signaling, therapy resistance, incidence of relapse and clinical outcome in human T-ALL. Furthermore, we emphasize that this potential association with clinical parameters might also be mediated by the tumor microenvironment as a result of increased sensitivity of leukemic T-cells towards cytokine induced signaling pathway activation. With this in mind, we provide an overview of small molecule inhibitors that might have clinical potential for the treatment of human T-ALL in the near future as a result of their ability to overcome steroid resistance thereby potentially increasing survival rates in this aggressive hematological neoplasm.

  • Clinical significance of altered collagen-receptor functioning in platelets with emphasis on glycoprotein VI
    Blood Rev. (IF 6.125) Pub Date : 2019-07-22
    Alan T. Nurden

    Much interest surrounds the receptors α2β1 and glycoprotein VI (GPVI) whose synchronized action mediates the attachment and activation of platelets on collagen, essential for preventing blood loss but also the most thrombogenic component of the vessel wall. Subject to density variations on platelets through natural polymorphisms, the absence of α2β1 or GPVI uniquely leads to a substantial block of hemostasis without causing major bleeding. Specific to the megakaryocyte lineage, GPVI and its signaling pathways are most promising targets for anti-thrombotic therapy. This review looks at the clinical consequences of the loss of collagen receptor function with emphasis on both the inherited and acquired loss of GPVI with brief mention of mouse models when necessary. A detailed survey of rare case reports of patients with inherited disease-causing variants of the GP6 gene is followed by an assessment of the causes and clinical consequences of acquired GPVI deficiency, a more frequent finding most often due to antibody-induced platelet GPVI shedding. Release of soluble GPVI is brought about by platelet metalloproteinases; a process induced by ligand or antibody binding to GPVI or even high shear forces. Also included is an assessment of the clinical importance of GPVI-mediated platelet interactions with fibrin and of the promise shown by the pharmacological inhibition of GPVI in a cardiovascular context. The role for GPVI in platelet function in inflammation and in the evolution and treatment of major illnesses such as rheumatoid arthritis, cancer and sepsis is also discussed.

  • Hematopoietic stem cell gene therapy: The optimal use of lentivirus and gene editing approaches
    Blood Rev. (IF 6.125) Pub Date : 2019-11-15
    Andrés Lamsfus-Calle, Alberto Daniel-Moreno, Guillermo Ureña-Bailén, Janani Raju, Justin S. Antony, Rupert Handgretinger, Markus Mezger

    Due to pioneering in vitro investigations on gene modification, gene engineering platforms have incredibly improved to a safer and more powerful tool for the treatment of multiple blood and immune disorders. Likewise, several clinical trials have been initiated combining autologous hematopoietic stem cell transplantation (auto-HSCT) with gene therapy (GT) tools. As several GT modalities such as lentivirus and gene editing tools have a long developmental path ahead to diminish its negative side effects, it is hard to decide which modality is optimal for treating a specific disease. Gene transfer by lentiviruses is the platform of choice for loss-of-mutation diseases, whereas gene correction/addition or gene disruption by gene editing tools, mainly CRISPR/Cas9, is likely to be more efficient in diseases where a tight regulation is needed. Therefore, in this review, we compiled pertinent information about lentiviral gene transfer and CRISPR/Cas9 gene editing, their evolution to a safer platform for HSCT, and their applications on other types of gene disorders based on the etiology of the disease and cell fitness.

  • Review of current transfusion therapy and blood banking practices1
    Blood Rev. (IF 6.125) Pub Date : 2019-07-25
    Emily K. Storch, Brian S. Custer, Michael R. Jacobs, Jay E. Menitove, Paul D. Mintz

    Transfusion Medicine is a dynamically evolving field. Recent high-quality research has reshaped the paradigms guiding blood transfusion. As increasing evidence supports the benefit of limiting transfusion, guidelines have been developed and disseminated into clinical practice governing optimal transfusion of red cells, platelets, plasma and cryoprecipitate. Concepts ranging from transfusion thresholds to prophylactic use to maximal storage time are addressed in guidelines. Patient blood management programs have developed to implement principles of patient safety through limiting transfusion in clinical practice. Data from National Hemovigilance Surveys showing dramatic declines in blood utilization over the past decade demonstrate the practical uptake of current principles guiding patient safety. In parallel with decreasing use of traditional blood products, the development of new technologies for blood transfusion such as freeze drying and cold storage has accelerated. Approaches to policy decision making to augment blood safety have also changed. Drivers of these changes include a deeper understanding of emerging threats and adverse events based on hemovigilance, and an increasing healthcare system expectation to align blood safety decision making with approaches used in other healthcare disciplines.

  • Modern management of relapsed and refractory aggressive B-cell lymphoma: A perspective on the current treatment landscape and patient selection for CAR T-cell therapy
    Blood Rev. (IF 6.125) Pub Date : 2019-11-14
    Veronika Bachanova, Miguel-Angel Perales, Jeremy S. Abramson

    Approximately 65% of patients with diffuse large B-cell lymphoma are cured with first-line therapy. However, approximately 10% to 15% exhibit primary refractory disease, and 20% to 25% experience relapse after initial response. Eligible patients receive second-line therapy followed by high-dose chemotherapy and an autologous hematopoietic stem cell transplant, previously the only potentially curative option for this population. Recently approved chimeric antigen receptor (CAR) T-cell therapies offer an alternative curative option for patients who have experienced a second-line or later relapse or whose disease is refractory. CD19-targeting CAR T cells are autologous T cells expressing an anti-CD19 CAR that, when reintroduced to the patient, identify and kill CD19+ B cells. Because of the novelty of CAR T-cell therapy and the complexity of this patient population, identification of ideal candidates is still being defined. This article summarizes 3 patient cases, focusing on the important aspects of patient selection for CAR T-cell therapy.

  • The golden age for patients in their golden years: The progressive upheaval of age and the treatment of newly-diagnosed acute myeloid leukemia
    Blood Rev. (IF 6.125) Pub Date : 2019-11-08
    Rory M. Shallis, Prajwal C. Boddu, Jan Philipp Bewersdorf, Amer M. Zeidan

    Most acute myeloid leukemia (AML) patients will be aged more than 65 years. Chronological aging is accompanied by decreasing stem cell and solid organ reserve as well as an increased incidence of medical comorbidity. For the older patient with AML, these patient-specific factors are compounded by an association with complexity of disease biology, chemoresistance, poor tolerance and early mortality with intensive induction therapy. However, the investigation and availability of therapies targeted against various molecular drivers of leukemogenesis, leukemic stem cell persistence, and chemoresistance have provided more options for the patient ineligible for intensive or classical induction therapy, often guided by age >60-65 years by some treatment algorithms. Many providers remain appropriately optimistic that such therapies may overtake the longstanding recommendation for frontline intensive therapy in certain circumstances. Traditional algorithms dichotomizing the optimal treatment modality based on AML patient age are aging themselves and are very likely to soon be outdated.

  • Thrombocytopenia in pregnancy: Diagnosis and approach to management
    Blood Rev. (IF 6.125) Pub Date : 2019-11-06
    Allyson M. Pishko, Lisa D. Levine, Douglas B. Cines

    Thrombocytopenia during pregnancy presents unique challenges for the hematologist. Obstetricians generally manage many of the pregnancy-specific etiologies, ranging from the benign (gestational thrombocytopenia) to the life-threatening (preeclampsia; hemolysis, elevated liver enzymes and low platelets syndrome; and acute fatty liver of pregnancy). However, hematologists may be consulted for atypical and severe presentations and to help manage non-pregnancy specific etiologies, including immune thrombocytopenia, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and antiphospholipid syndrome, among others, in which maternal and fetal risks must be considered. This review provides a general approach to the diagnosis and management of thrombocytopenia in pregnancy for the consulting hematologist.

  • Not all red cells sickle the same: Contributions of the reticulocyte to disease pathology in sickle cell anemia
    Blood Rev. (IF 6.125) Pub Date : 2019-11-05
    Marcus A. Carden, Ross M. Fasano, Emily Riehm Meier

    Sickle cell anemia (SCA) is associated with morbidity and early death. While the switch from fetal to sickle hemoglobin during the first months of life results in hemolytic anemia with reticulocytosis, the role of the reticulocyte in the pathophysiology and prognosis of SCA is not well-defined. Reticulocytes have unique cytoskeletal and membrane components that allow them to be distinguished from mature sickle erythrocytes in the circulation. Reticulocytes in patients with SCA are less dense than more mature and ‘sickled’ erythrocytes, and have increased adhesive properties. The circulating reticulocyte number in peripheral blood may assist in predicting disease severity in SCA; characterization of patient-specific reticulocyte properties during infancy and childhood may assist in predicting therapeutic response to therapies. Here, we review the biological and clinical data regarding reticulocytes and their potential impact on SCA pathophysiology and disease severity.

  • New developments in diagnosis, risk assessment and management in systemic amyloidosis
    Blood Rev. (IF 6.125) Pub Date : 2019-11-02
    Iuliana Vaxman, Angela Dispenzieri, Eli Muchtar, Morie Gertz

    Amyloidosis is a group of disorders characterized by a misfolded protein that deposits in organs and compromise their function. Clinician should have a high index of suspicion because in most cases, the clinical picture is non-specific. Typing of amyloid is of utmost importance and should be an integral part of accurately diagnosing a patient. AL amyloidosis is the most common systemic amyloidosis in the western world in which the misfolded proteins are immunoglobulin light chains secreted by clonal plasma cells. New data about prognostication of AL amyloidosis patients are accumulating. The treatment goal is to eradicate the amyloidogenic plasma cell clone, by using high dose melphalan and/or novel agents (proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies against CD38). Early diagnosis is important for effectively treating the patient as late diagnosis hampers chances for organ recovery. ATTR amyloidosis is less recognized but is increasingly seen due to better recognition and improved diagnostic tools. New data about treatment options (patisiran, inotersen and tafamidis) have recently been published and are discussed.

  • Immunomodulatory effect of ibrutinib: Reducing the barrier against fungal infections
    Blood Rev. (IF 6.125) Pub Date : 2019-10-31
    Rossana Maffei, Monica Maccaferri, Laura Arletti, Stefania Fiorcari, Stefania Benatti, Leonardo Potenza, Mario Luppi, Marasca Roberto

    The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is increasingly used in the treatment of chronic lymphocytic leukemia (CLL). Moreover, very promising results have been reported in other B-cell malignancies, including primary central nervous system lymphoma (PCNSL). Although well-tolerated in the majority of patients, ibrutinib demonstrates in some cases troublesome toxicities, including invasive fungal infections (IFIs). In the present review, we summarize clinical manifestations of IFIs in patients treated with ibrutinib, generally characterized by an early onset, mild clinical manifestations, asymptomatic/low symptomatic pulmonary localization and high incidence of central nervous system (CNS) involvement. IFI risk appears particularly increased in patients receiving ibrutinib associated with other immune modulator agents, especially with steroids or immune-chemotherapy. Moreover, the immunomodulatory effect of ibrutinib is described, pointing the attention on the involvement of specific molecules targeted by ibrutinib in innate and adaptive response to fungal infection. Overall, the findings indicate the ibrutinib may rapidly impair innate immune cell functions, while concomitantly restoring an effective protective potential of adaptive immune compartment. A correct awareness, especially when other predisposing factors are present, is warranted about the potential risk of IFIs in ibrutinib-treated patients.

  • Cereblon binding molecules in multiple myeloma.
    Blood Rev. (IF 6.125) Pub Date : 2015-04-07
    K M Kortüm,Y X Zhu,C X Shi,P Jedlowski,A K Stewart

    Immunomodulation is an established treatment strategy in multiple myeloma with thalidomide and its derivatives lenalidomide and pomalidomide as its FDA approved representatives. Just recently the method of action of these cereblon binding molecules was deciphered and results from large phase 3 trials confirmed the backbone function of this drug family in various combination therapies. This review details the to-date knowledge concerning mechanism of IMiD action, clinical applications and plausible escape mechanisms in which cells may become resistant/refractory to cereblon binding molecule based treatment.

  • Recombinant factor VIIa (rFVIIa) and its use in severe bleeding in surgery and trauma: a review.
    Blood Rev. (IF 6.125) Pub Date : 2003-12-31
    Mike Grounds

    Haemorrhage is a potential complication of any surgical procedure, presenting a major challenge to the surgeon and anaesthetist. In addition, uncontrolled bleeding accounts for at least 40% of the mortality associated with military and civilian trauma. Despite the widespread availability of standard interventions for the control of bleeding in such circumstances, there still remains an urgent need for an effective haemostatic agent that is safe, easy to use, and able to enhance local thrombotic processes without causing generalised arterial or venous thrombosis. Recombinant factor VIIa (rFVIIa; NovoSeven) has been successfully used in the management of haemophilia patients with inhibitors for many years. This review will explore its use in the control of surgery- and trauma-associated haemorrhage in patients without pre-existing coagulopathy, and will highlight the growing realisation that rFVIIa may have a major role not only as a treatment for haemophilia, but also as a universal haemostatic agent. This paper will also briefly explore those unanswered questions that should be resolved by future trials aiming to further clarify the safety, efficacy, and optimal dosing strategies of rFVIIa in the surgical and trauma settings.

  • Haemopoietic stem cell transplants: the impact of haemorrhagic complications.
    Blood Rev. (IF 6.125) Pub Date : 2003-12-31
    Andrea Bacigalupo

    Acute graft-versus-host disease (GVHD) is the most important complication of allogeneic haemopoietic stem cell transplantation (HSCT), increasing susceptibility to haemorrhage and risk of early mortality. We evaluated 807 allogeneic HSCT patients to assess both the association between bleeding and GVHD, and the influence of haemorrhagic complications on clinical outcome. Up to 55% of patients with grade III-IV GVHD experienced bleeding, compared with 23% of patients with grades 0-l. Furthermore, 45% of patients receiving non-HLA-identical transplants suffered haemorrhage, whereas only 23% of patients receiving transplants from HLA-identical donors experienced bleeding. This can be explained by the higher incidence of severe GVHD among recipients of non-HLA-identical transplants. Our findings also demonstrated that haemorrhagic complications--particularly bleeding from the GI tract--markedly increase patient mortality. An ongoing, multi-centre, randomised, double-blind trial is currently investigating the efficacy and safety of recombinant factor VIIa (rFVIIa; NovoSeven) in the treatment of HSCT-associated bleeding. The trial will examine the ability of three dose levels of rFVIIa to reduce--or even eliminate entirely--the incidence and severity of haemorrhage following such procedures. A total enrollment of 100 patients is anticipated, and preliminary data are expected at the end of 2003.

  • A cell-based model of coagulation and the role of factor VIIa.
    Blood Rev. (IF 6.125) Pub Date : 2003-12-31
    Maureane Hoffman

    Our cell-based model of haemostasis replaces the traditional 'cascade' hypothesis, and proposes that coagulation takes place on different cell surfaces in three overlapping steps: initiation, amplification, and propagation. In highlighting the importance of cellular control during coagulation, the cell-based model allows a more thorough understanding of how haemostasis works in vivo, and sheds light on the pathophysiological mechanisms behind certain coagulation disorders. For instance, this model proposes that haemophilia involves a failure of platelet-surface FXa generation, leading to a lack of platelet-surface thrombin production. Our data suggest that high-dose FVIIa is able to bind weakly to activated platelets, independently of tissue factor, in order to generate sufficient amounts of FXa to support a burst bf thrombin generation in the absence of FIXa/FVIIIa. The considerable success of high-dose recombinant FVIIa (rFVIIa; NovoSeven, Novo Nordisk, Copenhagen, Denmark) as a therapy for patients with haemophilia and inhibitors has led to its use in a growing number of alternative indications. We believe that even in the presence of the FIXa/FVIIIa complex, rFVIIa may be able to enhance both FXa and FIXa levels on the surface of activated platelets, thus increasing the production of thrombin.

  • The intriguing contribution of white blood cells to sickle cell disease - a red cell disorder.
    Blood Rev. (IF 6.125) Pub Date : 2003-12-20
    Iheanyi Okpala

    Sickle cell disease (SCD) is characterized by a point mutation that replaces adenine with thymidine in the sixth codon of the beta-globin gene, a unique morphological abnormality of red blood cells, vaso-occlusion with ischaemic tissue injury, and susceptibility to infections. Vascular lumen obstruction in SCD results from interaction of erythrocytes, leukocytes, platelets, plasma proteins, and the vessel wall. The disease phenotype is a product of various genes and environmental factors acting in concert with the protein lesion underlying the red cell anomaly. The severity of SCD increases with leukocyte count. The biological basis and therapeutic implications of this relationship are discussed. Leukocytes contribute to SCD by adhering to blood vessel walls and obstructing the lumen, aggregating with other blood cells with more effective blockage of the lumen, stimulating the vascular endothelium to increase its expression of ligands for adhesion molecules on blood cells, and causing tissue damage and inflammatory reaction which predispose to vaso-occlusion. Patients with impaired ability of leukocytes to kill microbes are more prone to infections; which precipitate sickle cell crisis. Reduction of leukocyte count ameliorates SCD. Similarly, targeted blockade or reduced synthesis of specific leukocyte adhesion molecules and their ligands might confer clinical benefit in SCD.

  • The therapy of relapsed acute leukaemia in adults.
    Blood Rev. (IF 6.125) Pub Date : 2003-12-20
    Mark R Litzow

    Although the cure of acute leukaemia has improved significantly, many patients will still relapse and die. The unraveling of the molecular pathogenesis of acute leukaemia has lead to the identification of new prognostic factors and improved the detection of minimal residual disease. The treatment of relapsed acute leukaemia with chemotherapy remains unsatisfactory. Allogeneic or autologous blood and marrow transplant (BMT) can cure a subset of patients with relapsed acute leukaemia. The identification of the graft-vs-leukaemia (GVL) effect has lead to the development of donor lymphocyte infusions to re-induce remission in patients with relapsed leukaemia after allogeneic BMT and also stimulated the development of the less toxic nonmyeloablative allogeneic transplant approach. The identification of molecular targets of therapy and the development of monoclonal antibody-directed therapy has generated optimism. It is possible that combinations of chemotherapy, molecularly directed therapy, and immunotherapy may be combined to cure an increasing proportion of patients with acute leukaemia.

  • Therapy for immunoglobulin light chain amyloidosis: the new and the old.
    Blood Rev. (IF 6.125) Pub Date : 2003-12-20
    Morie A Gertz,Martha Q Lacy,Angela Dispenzieri

    An accurate diagnosis of amyloidosis and its subtype classification are essential for disease prognostication and treatment. In primary amyloidosis, overall median survival is approximately 2 years and may be less in patients with cardiomyopathy. Current therapy for primary amyloidosis is suboptimal. Controlled studies suggest that treatment with melphalan and prednisone may provide marginal survival benefit. A more aggressive approach such as autologous hematopoietic stem cell transplantation may offer potential for long-term benefit. Although patients undergoing autologous hematopoietic stem cell transplantation are highly selected, response rates can approach 60%, and patients with amyloidosis who respond to treatment have potential for long-term survival. New treatment modalities that were shown to have antitumor activity in multiple myeloma (high-dose dexamethasone and thalidomide) may also be of therapeutic value in primary amyloidosis. Systemic chemotherapy would not be expected to have any beneficial effect on other forms of amyloid and carries significant risk.

  • Activation of factor VIII and mechanisms of cofactor action.
    Blood Rev. (IF 6.125) Pub Date : 2003-12-20
    Philip J Fay

    The factor VIII procofactor circulates as a metal ion-dependent heterodimer of a heavy chain and light chain. Activation of factor VIII results from limited proteolysis catalyzed by thrombin or factor Xa, which binds the factor VIII substrate over extended interactive surfaces. The proteases efficiently cleave factor VIII at three sites, two within the heavy and one within the light chain resulting in alteration of its covalent structure and conformation and yielding the active cofactor, factor VIIIa. The role of factor VIIIa is to markedly increase the catalytic efficiency of factor IXa in the activation of factor X. This effect is manifested in a dramatic increase in the catalytic rate constant, k(cat), by mechanisms that remain poorly understood.

  • Human cytomegalovirus-specific immunity following haemopoietic stem cell transplantation.
    Blood Rev. (IF 6.125) Pub Date : 2003-10-15
    Maher K Gandhi,Mark R Wills,J G Patrick Sissons,Andrew J Carmichael

    The herpesvirus Human Cytomegalovirus (HCMV) is an important opportunistic infection in recipients of allogeneic haemopoietic stem cell transplants, in whom HCMV-specific CD8+ and CD4+ T-cell responses are impaired. The nature of the HCMV-specific T-cell response in healthy virus carriers has been characterised in detail. High frequencies of circulating CD8+ T-cells that recognise defined viral peptides are maintained for years, and include individual CD8+ clones that have undergone extensive clonal expansion and phenotypic diversification in vivo. Following stem cell transplantation, the kinetics of HCMV-specific CD8+ T-cell reconstitution in the recipient are related to the presence or absence of antigen-experienced CD8+ T-cells transferred via the allograft, and to the presence of the virus in the recipient. We discuss recent progress in our understanding of HCMV-specific immunity in healthy virus carriers and in recipients after alloSCT.

  • Treatment of human immunodeficiency virus-related lymphoma with haematopoietic stem cell transplantation.
    Blood Rev. (IF 6.125) Pub Date : 2003-10-15
    Arturo Molina,John Zaia,Amrita Krishnan

    The advent of highly active antiretroviral therapy (HAART) and its co-administration with chemotherapy in patients with human immunodeficiency virus (HIV)-related lymphoma has lead to the exploration of potentially curative combination chemotherapy and myeloablative therapy followed by autologous haematopoietic stem cell transplantation (ASCT). Applying the same principles used for patients with HIV-negative aggressive lymphoma, in 1998 we developed a program of high-dose therapy and ASCT at City of Hope for patients with HIV-related lymphoma and Hodgkin's disease. Our studies have primarily included patients with chemosensitive lymphoma in relapse or first remission with poor-risk features at diagnosis. Filgrastim (G-CSF)-primed peripheral blood stem cell mobilization and apheresis have been successful while patients were receiving HAART and chemotherapy. To date, ASCT has been performed in 19 patients with HIV-related lymphoid malignancies, representing the largest single-institution experience reported to date. Most patients received a chemotherapy-based conditioning regimen consisting of high-dose carmustine, etoposide and cyclophosphamide. Early infections, namely bacteremias and neutropenic fever were similar to those observed in the HIV-negative transplant setting. Opportunistic infections were rare and easily treatable. There were three early deaths, two from relapsed lymphoma and one from multi-organ failure in an older patient. The remaining 16 patients are alive and in remission. In summary, ASCT is well tolerated, can result in long-term remissions, and is potentially curative in selected HIV-related lymphoma patients with chemosensitive relapse and high-risk disease in first remission defined by the age-adjusted International Prognostic Index criteria (i.e., two or three of the following: elevated LDH, advanced stage, and poor performance status). Acquisition of resistance to HAART remains as a potential problem for HIV-positive patients who are cured of their lymphoma.

  • Receptor tyrosine kinases in normal and malignant haematopoiesis.
    Blood Rev. (IF 6.125) Pub Date : 2003-10-15
    John T Reilly

    Haematopoiesis is controlled by a number of growth factors and cytokines, a number of which act through binding to high-affinity receptor tyrosine kinases (RTKs). Approximately 20 different RTK classes have been identified, all of which share a similar structure that includes a ligand binding extracellular domain, a single transmembrane domain and an intracellular tyrosine kinase domain. Recent studies have linked an increasing number of mutations in the RTKs to the pathogenesis of both acute and chronic leukaemia. For example, the FLT3 receptor, a RTK class III, is the most commonly mutated gene in acute myeloid leukaemia, while c-kit mutations are strongly linked to the development of mast cell malignancy. This review summarizes the RTK classes that are known to be expressed on normal haematopoietic tissue and highlights the many 'gain-of-function' mutations involved in leukaemogenesis. It is to be hoped that this knowledge will provide important new insights for targeted therapy in leukaemia.

  • Stem cell transplantation for multiple sclerosis: what is the evidence?
    Blood Rev. (IF 6.125) Pub Date : 2003-10-15
    Athanasios Fassas,Vassilios K Kimiskidis

    Experimental and clinical observations have indicated that high-dose immunosuppression followed by autologous stem cell transplantation (ASCT) can induce remissions in severe, refractory, autoimmune diseases including multiple sclerosis (MS), a T cell-mediated autoimmune disorder against CNS myelin components, causing severe chronic disability. Control of the disease is unsatisfactory in most of the patients, especially those with rapidly evolving relapsing-remitting course and those with chronic progressive disease. The rationale for treating autoimmune diseases with ASCT is based on the immunosuppressive and immunomodulating effects of ASCT which may shift the immunological balance towards disease quiescence, a hypothesis supported by the results of ASCT in animal models of MS and by clinical observations in MS patients transplanted for concurrent malignancies. A number of phase I-II studies of ASCT in patients with active MS, conducted worldwide since 1995, and a comprehensive analysis of 85 patients, recently reported by the European Group for Blood and Marrow Transplantation (EBMT), have shown the feasibility of the method, a prominent anti-inflammatory effect on magnetic resonance imaging (MRI) disease, and a possible clinical benefit for active and refractory cases. The impact on MRI disease parameters appears superior with ASCT than with conventional therapies but the clinical results, in terms of stabilization of disease and prevention of disability, need to be validated in prospective, controlled trials. The procedure is also associated with a transplant-related mortality risk, of about 5% in high-risk cases, i.e., in older patients, those with high disability scores, those receiving strong myeloablative conditioning regimens and those undergoing intensive in vivo or ex vivo T cell-depletion. Therefore, it could be recommended for the treatment of a chronic, non-lethal, disease like MS only if it proved superior to standard therapies. A randomized trial is now launched by the EBMT to compare ASCT to mitoxantrone, currently regarded as one of the best available treatments, in properly selected patients having high chance of response at minimal mortality risk.

  • Stem cells and immune reconstitution in AIDS.
    Blood Rev. (IF 6.125) Pub Date : 2003-10-15
    David T Scadden

    The hematopoietic system generally has reserve sufficient to tolerate significant insult and regenerative capacity to overcome most damage due to infectious agents. However, HIV infection results in a progressive decline in hematopoietic function and even in the context of potent, anti-retroviral therapy is able to only incompletely reconstitute immune function. The ability of the immune system to respond to HIV itself remains compromised, a defect that leaves infected individuals with a lifelong dependence on medications. The capability of stem cells and the thymus to restore function and their limitations in the context of HIV infection are discussed in this review.

  • Dyskeratosis congenita: its link to telomerase and aplastic anaemia.
    Blood Rev. (IF 6.125) Pub Date : 2003-10-15
    Inderjeet Dokal,Tom Vulliamy

    Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome exhibiting considerable clinical and genetic heterogeneity. X-linked recessive, autosomal dominant and autosomal recessive forms are recognised. The gene mutated in X-linked DC (DKC1) encodes a highly conserved nucleolar protein called dyskerin. Dyskerin associates with the H/ACA class of small nucleolar RNAs which are important in guiding the conversion of uracil to pseudouracil in ribosomal RNA. Dyskerin also associates with the RNA component of telomerase (hTR) which is important in the maintenance of telomeres. Mutations in hTR were recently demonstrated in patients with autosomal dominant DC and in a subset of patients with aplastic anaemia (AA) but without other diagnostic features of DC. This discovery demonstrates that both DC and a subset of AA are due to a defect in telomerase. The link between DC and AA and in turn to defective telomerase suggests that treatments directed at correction of telomerase activity might benefit DC/AA patients who do not respond to conventional therapy.

  • Congenital neutropenia.
    Blood Rev. (IF 6.125) Pub Date : 2003-10-15
    Philip James Ancliff

    Congenital neutropenia is strictly defined as neutropenia present at birth. However, it is more generally used to describe neutropenia secondary to inherited genetic mutations. This review will discuss the presentation of such children and the various causes of congenital neutropenia. In particular, it will focus on severe congenital neutropenia (SCN) and the recent discovery of mutations in the gene encoding neutrophil elastase in the majority of cases of SCN. The potential mechanisms of pathogenesis and of transformation to leukaemia will be discussed. Shwachman-Diamond Syndrome and other less common causes of congenital neutropenia will also be reviewed. Finally, an approach to the child with potential congenital neutropenia will be presented.

  • Anaemia and red blood cell transfusion in the critically ill patient.
    Blood Rev. (IF 6.125) Pub Date : 2003-10-15
    S A McLellan,D B L McClelland,T S Walsh

    Anaemia is a common finding in critically ill patients. There are often multiple causes. Obvious causes include surgical bleeding and gastrointestinal haemorrhage but many patients have no overt bleeding episodes. Phlebotomy can be a significant source of blood loss. In addition, critically ill patients have impaired erythropoiesis as a consequence of blunted erythropoietin production and direct inhibitory effects of inflammatory cytokines. The ability of a patient to tolerate anaemia depends on their clinical condition and the presence of any significant co-morbidity; maintenance of circulating volume is of paramount importance. There is no universal transfusion trigger. Current guidelines for critically ill and perioperative patients advise that at Hb values <70 g/L red blood cell transfusion is strongly indicated and at Hb values >100 g/L transfusion is unjustified. For patients with Hb values in the range 70 to 100 g/L the transfusion trigger should be based on clinical indicators. Most stable critically ill patients can probably be managed with a Hb concentration between 70 and 90 g/L. Uncertainties exist concerning the most appropriate Hb concentration for patients with significant cardio-respiratory disease.

  • Immunobiology of acute graft-versus-host disease.
    Blood Rev. (IF 6.125) Pub Date : 2003-10-15
    Pavan Reddy,James L M Ferrara

    Graft-versus-host disease (GVHD) has been the primary limitation to the wider application of allogeneic bone marrow transplantation (BMT). The immunobiology of acute GVHD is complex and can be conceptualized to be a three-step process. In step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to the damage and activation of host tissues and induces the secretion of inflammatory cytokines TNF-alpha and IL-1. As a consequence expression of MHC antigens and adhesion molecules is increased, thus enhancing the recognition of host alloantigens by donor T cells. Donor T-cell activation in step 2 is characterized by donor T-cell interaction with host APCs and subsequent proliferation, differentiation, and secretion of cytokines. Cytokines such as IL-2 and IFN-gamma enhance T-cell expansion, induce cytotoxic T cells (CTL) and natural killer (NK) cell responses, and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. These inflammatory cytokines in turn stimulate production of inflammatory chemokines, thus recruiting effector cells into target organs. In step 3, effector functions of mononuclear phagocytes are triggered via a secondary signal provided by lipopolysaccharide (LPS) that leaks through the intestinal mucosa damaged during step 1. This mechanism may result in the amplification of local tissue injury and further promotion of an inflammatory response, which, together with the CTL and NK components, leads to target tissue destruction in the transplant host.

  • The management of perioperative bleeding.
    Blood Rev. (IF 6.125) Pub Date : 2003-06-24
    M B C Koh,Beverley J Hunt

    Excess perioperative bleeding remains a major complication following surgery, resulting in increased morbidity and mortality. The principal causes of non-surgical haemostatic perioperative bleeding are a pre-existing undetected bleeding disorder, related to the nature of the operation itself or from coagulation abnormalities arising from massive blood loss. Very often, it is a combination and coexistence of various pathologies. Identifying patients at risk remains a major component of preventing excessive blood loss. Understanding the haemostatic changes occurring in the perioperative period, especially in complex procedures like cardiopulmonary bypass and orthotopic liver transplantation is crucial in developing new strategies for the management of perioperative bleeding. Pharmacological interventions, especially aprotinin, tranexamic acid, desmopressin and increasingly, recombinant VIIa are being used both in prophylaxis and therapeutically to stop bleeding. The use of near patient testing like thromboelastography and platelet function analyser has allowed for more detailed assessment of the various steps of haemostasis. One of the main goals is to reduce the usage of allogeneic blood transfusion and its attendant risks.

  • The paradox of hemoglobin SC disease.
    Blood Rev. (IF 6.125) Pub Date : 2003-06-24
    Ronald L Nagel,Mary E Fabry,Martin H Steinberg

    Homozygous HbC gene results only in mild hemolytic anemia. In HbSC disease red cells contain equal levels of HbS and HbC. It is a paradox that HbSC exhibit a moderately severe phenotype in spite of being a mixture of HbS trait and HbC trait, neither of which has significant pathology. Why does the combination of these two Hbs result in a serious disease? The short answer is that HbC enhances, by dehydrating the SC red cell, the pathogenic properties of HbS, resulting in a clinically significant disorder, but somewhat milder that sickle cell anemia (SCA). Nevertheless, retinnitis proliferans, osteonecrosis, and acute chest syndrome have equal or higher incidence in HbSC disease compared to SCA. This pathogenic trick is accomplished by HbC inducing, by mechanisms not fully understood, an increase in the activity of K:Cl cotransport that induces the lost of K(+) and consequently of intracellular water. This event creates a sufficient increase of MCHC, so that the lower levels of HbS found in SC red cells can polymerize rapidly and effectively. This situation offers a unique opportunity: if we could inhibit the effect of HbC on K(+) transport we can cure the disease.

  • Hematopoietic stem cell transplantation in sickle cell disease.
    Blood Rev. (IF 6.125) Pub Date : 2003-06-24
    Christiane Vermylen

    Since the first report of a young girl affected by sickle cell anemia, treated successfully by bone marrow transplantation (BMT) for acute myeloid leukemia, more than 200 patients have been transplanted worldwide for sickle cell anemia. The disease-free survival (DFS) is good (80-85% in several series), even though many children who received allografts had already significant sickle-related complications. The best results are obtained in young children who have HLA-identical sibling donors and are transplanted early in the course of the disease (DFS: 93%). Future directions in the field of stem cell transplantation of sickle cell anemia include (1) the establishment of new protocols with less toxicity, but still effective, (2) adapted conditioning regimen for adult patients, and (3) new sources of stem cells for broader application: umbilical cord blood and volunteer unrelated donors.

  • The graft versus leukemia response after allogeneic hematopoietic stem cell transplantation.
    Blood Rev. (IF 6.125) Pub Date : 2003-06-24
    Stanley R Riddell,Carolina Berger,Makoto Murata,Sophia Randolph,Edus H Warren

    It is now well established that the efficacy of allogeneic hematopoietic stem cell transplant for eradicating a variety of hematologic malignancies is related to antitumor activity mediated by donor immune cells contained in the stem cell graft. Recent studies have provided fundamental insights into the nature of the effector cells and target molecules that are responsible for the graft versus tumor effect. T cells specific for minor histocompatibility antigens can mediate potent antitumor activity but are also responsible for graft versus host disease (GVHD). The molecular characterization of minor antigens has suggested ways of potentially separating antitumor activity from GVHD. The challenge for the future is to continue to build on our understanding of the allogeneic graft versus tumor effect and develop strategies that can be incorporated into clinical practice to augment this effect without GVHD.

  • Monoclonal antibody therapy for lymphoma.
    Blood Rev. (IF 6.125) Pub Date : 2003-06-24
    Peter Campbell,Robert Marcus

    Monoclonal antibodies are an exciting advance in the treatment of lymphoma. They are safe and well-tolerated, and exhibit little cross-resistance with conventional chemotherapeutic agents. In indolent lymphomas, antibody therapy has shown useful response rates, both as first-line therapy and in relapsed disease. Follicular lymphomas appear to be particularly sensitive to rituximab, and chronic lymphocytic leukaemia to alemtuzumab. In aggressive lymphomas, the addition of rituximab to CHOP chemotherapy significantly lengthens disease-free and overall survival compared to CHOP alone as first-line therapy. Newer agents, including radiolabelled antibodies, immunotoxin-linked antibodies and antibodies against novel target antigens are showing promise in phase I and II trials in a variety of clinical settings.

  • Primary cutaneous lymphomas: a review with current treatment options.
    Blood Rev. (IF 6.125) Pub Date : 2003-06-24
    Christiane Querfeld,Joan Guitart,Timothy M Kuzel,Steven T Rosen

    Primary cutaneous T- and B-cell lymphomas are a heterogenous group of diseases with varied clinical presentations and prognosis. The use of new molecular, histological, and clinical criteria have enhanced the recognition of primary cutaneous T- and B-cell lymphomas. Compared to their nodal counterpart they have a different clinical behavior and therefore require a different treatment approach. Independent predictive factors identified clinically, histologically, and by immunopheno- and immunogenotyping are essential to assess the appropriate treatment for each subtype. The European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Study Group provide a classification of cutaneous lymphomas taking into account of the histological and molecular features. Based on this classification we will provide a summary of the current medical literature in diagnosis, treatment, and prognosis for primary cutaneous lymphomas with emphasis on new treatment strategies.

  • Farnesyl transferase inhibitors in myeloid malignancies.
    Blood Rev. (IF 6.125) Pub Date : 2003-06-24
    Jeffrey E Lancet,Judith E Karp

    Farnesyl transferase inhibitors (FTIs) are a novel class of anti-cancer agents that competitively inhibit farnesyl protein transferase (FPT), and are currently being developed and tested across a wide range of human cancers. Hematologic malignancies, particularly those of myeloid origin, are reasonable disease targets in that they likely overexpress relevant biologic targets, such as Ras, mitogen-activated protein kinase (MAPK), or AKT, that depend upon FPT activity to promote proliferation and survival. Phase I clinical trials using FTIs in acute myelogenous leukemia (AML) and other myeloid malignancies have been performed, demonstrating enzyme target inhibition, low toxicity, and promising response rates. These findings have prompted further development in phase II trials, in order to clarify the response rate and to identify the actual downstream signal transduction targets that may be modified by these agents. It is anticipated that such information will ultimately define the optimal roles of FTIs in patients with AML and other myeloid disorders, facilitate the incorporation of FTIs into current therapeutic strategies for myeloid malignancies, and provide insight into effective methods of combining FTIs with other signal transduction inhibitors.

  • Safety of the blood supply: role of pathogen reduction.
    Blood Rev. (IF 6.125) Pub Date : 2003-03-19
    Yan Yun Wu,Edward L Snyder

    Even though the blood supply is very safe, the risk of transfusion transmitted disease is not zero. To improve the safety of the blood supply, pathogen reduction (PR) technology has been developed. The principle of most current PR strategies involves modifying DNA or RNA templates and making them inaccessible to DNA or RNA polymerase. Several platforms of pathogen reduction are available including psoralens, alkylating compounds, binary ethyleneimine-like compounds, riboflavin, methylene blue, and solvent-detergent treatment. PR systems have been designed for RBC, plasma, and platelets. PR technology has been found to be effective for a variety of pathogens including lipid-enveloped and non-enveloped viruses, bacteria and parasites. Pre-clinical studies and Phase III clinical trials to evaluate the efficacy and safety of these PR technologies are currently ongoing.

  • The role of hydroxyurea in the management of sickle cell disease.
    Blood Rev. (IF 6.125) Pub Date : 2003-03-19
    Sally C Davies,Annette Gilmore

    Sickle cell disease (SCD) is one of the most common genetic diseases with some 250,000 new births each year. Most patients suffer intermittent pain crises and life-threatening events while life expectancy is considerably reduced. Until the last decade management was purely preventative or supportive aimed at symptom control. Apart from stem cell transplant, there is no cure but the oral chemotherapeutic drug hydroxyurea (HU) has now established a role in ameliorating the disease and improving life expectancy for most patients. There are side effects and risks of HU treatment in SCD but for moderate and severely affected patients, the benefits can be significant.

  • The molecular pathogenesis of acute promyelocytic leukaemia: implications for the clinical management of the disease.
    Blood Rev. (IF 6.125) Pub Date : 2003-03-19
    Anita R Mistry,Eva W Pedersen,Ellen Solomon,David Grimwade

    Acute promyelocytic leukaemia (APL) is characterised by chromosomal rearrangements of 17q21, leading to fusion of the gene encoding retinoic acid receptor alpha (RARalpha) to a number of alternative partner genes (X), the most frequent of which are PML (>95%), PLZF (0.8%) and NPM (0.5%). Over the last few years, it has been established that the X-RARalpha fusion proteins play a key role in the pathogenesis of APL through recruitment of co-repressors and the histone deacetylase (HDAC)-complex to repress genes implicated in myeloid differentiation. Paradoxically, the X-RARalpha fusion protein has the potential to mediate myeloid differentiation at pharmacological doses of its ligand (all trans-retinoic acid (ATRA)), which is dependent on the dissociation of the HDAC/co-repressor complex. Arsenic compounds have also been shown to be promising therapeutic agents, leading to differentiation and apoptosis of APL blasts. It is now apparent that the nature of the RARalpha-fusion partner is a critical determinant of response to ATRA and arsenic, underlining the importance of cytogenetic and molecular characterisation of patients with suspected APL to determine the most appropriate treatment approach. Standard protocols involving ATRA combined with anthracycline-based chemotherapy, lead to cure of approximately 70% patients with PML-RARalpha-associated APL. Patients at high risk of relapse can be identified by minimal residual disease monitoring. The challenge for future studies is to improve complete remission rates through reduction of induction deaths, particularly due to haemorrhage, identification of patients at high risk of relapse who would benefit from additional therapy, and identification of a favourable-risk group, for which treatment intensity could be reduced, thereby reducing risks of treatment toxicity and development of secondary leukaemia/myelodysplasia. With the advent of ATRA and arsenic, APL has already provided the first example of successful molecularly targeted therapy; it is hoped that with further understanding of the pathogenesis of the disease, the next decade will yield further improvements in the outlook for these patients.

  • Veno-occlusive disease: cytokines, genetics, and haemostasis.
    Blood Rev. (IF 6.125) Pub Date : 2003-03-19
    Jason A Coppell,Simon A Brown,David J Perry

    Hepatic veno-occlusive disease (VOD) is a major cause of morbidity and mortality following high dose cytotoxic therapy for stem cell transplantation (SCT). Pre-existing liver damage, SCT-related therapy, and genetic polymorphisms all appear to increase the risk of developing VOD. Studies of biological markers during SCT suggest that cytokines, haemostasis, and hepatic drug metabolism via the glutathione pathway are all involved in the pathogenesis of VOD. Until recently, treatment options were limited and experimental therapies directed at the pathogenesis of the disease were mostly unsuccessful. However, Defibrotide, a relatively new agent that has modulatory effects on vascular endothelium, cytokine release, and haemostasis, has been used with some success in the management and prophylaxis of VOD. In the future, a better understanding of genetic polymorphisms and biological markers which may be important in the pathogenesis of VOD, may enable us to predict which patients are most likely to be affected.

  • Screening and genetic diagnosis of haemoglobin disorders.
    Blood Rev. (IF 6.125) Pub Date : 2002-12-20
    J M Old

    The inherited haemoglobinopathies are large group of disorders that include the thalassaemias and sickle cell disease. Carrier detection methods must be able to detect alpha-, beta- and deltabeta-thalassaemias, HPFH disorders and haemoglobin variants. Carrier diagnosis involves the accurate measurement of MCH, MCV, Hb A(2) and Hb F values in combination with an understanding of the haematological characteristics of the different types of thalassaemia genes and their interactions. The majority of the common thalassaemia mutations and abnormal haemoglobins can be identified by PCR-based techniques. The main applications of molecular analysis for carrier diagnosis are: the analysis of alpha-thalassaemia mutations by gap-PCR to discriminate between heterozygous alpha-thalassaemia and homozygous alpha-thalassaemia; the identification of beta-thalassaemia mutations for patients requiring prenatal diagnosis and for the prediction of the severity of the clinical phenotype of homozygous beta-thalassaemia; to discriminate between deltabeta-thalassaemia and HPFH deletions by gap-PCR.

  • Structural basis of the fibrinogen-fibrin transformation: contributions from X-ray crystallography.
    Blood Rev. (IF 6.125) Pub Date : 2002-12-20
    Russell F Doolittle

    During the past several years, a number of crystal structures have been determined of fragments from fibrinogen and fibrin and, most recently, a structure of a native fibrinogen. One feature of the fibrinogen molecule that has emerged from these studies has to do with its "loose ends," segments of the molecule that are extremely mobile and not discernable by X-ray crystallography. Some, if not all, of this flexibility is functionally important. Small synthetic peptides based on mobile parts of fibrinogen exposed by the action of thrombin have contributed significantly to these studies and may yet prove useful therapeutically. In the end, although crystal structures have added greatly to our understanding of fibrin formation, much still needs to be unraveled about how clots form.

  • Monoclonal antibodies combined to chemotherapy for the treatment of patients with lymphoma.
    Blood Rev. (IF 6.125) Pub Date : 2002-12-20
    Bertrand Coiffier

    Humanized monoclonal antibodies have transformed the treatment of patients with lymphomas. The first application of these new drugs appeared less than 10 years ago but currently one patient will certainly receive them once or several time during the evolution of his disease. This review will cover the use of these monoclonal antibodies alone or in combination with chemotherapy. Rituximab, an unconjugated anti-CD20 chimeric antibody, is certainly the most widely used but other unconjugated or radiolabeled monoclonal antibodies catch up quickly. If there are randomized studies demonstrating the benefit of adding these drugs to the treatment of patients with lymphoma, very few studies have compared the activity of the different monoclonal antibodies. A lot of questions needs to be answered before the best setting of these drugs will be known.

  • Molecular targets in acute myelogenous leukemia.
    Blood Rev. (IF 6.125) Pub Date : 2002-12-20
    Derek L Stirewalt,Soheil Meshinchi,Jerald P Radich

    Acute myeloid leukemia (AML) remains the most common form of leukemia and the most common cause of leukemia death. Although conventional chemotherapy can cure between 25 and 45% of AML patients, most patients will either die of relapse or die from the complications associated with treatment. Thus, more specific and less toxic treatments for AML patients are needed. Recently, a small molecular inhibitor (STI571 or Gleevec) that targets the BCR-ABL gene was found to have a dramatic clinical effect in patients with chronic myelogenous leukemia (CML). These results have encouraged investigators to search for additional small molecular inhibitors and other targeted therapies that may be applicable to other forms of leukemia. In this review, we examine some of the signaling pathways that are aberrantly regulated in AML, focusing on the tyrosine kinase/RAS/MAP kinase and JAK/STAT pathways. After reviewing these two pathways, we explore some of the targeted therapies directed at these pathways that are under development for AML, many of which are already in clinical trials.

  • Thrombocytopenia in pregnancy: differential diagnosis, pathogenesis, and management.
    Blood Rev. (IF 6.125) Pub Date : 2002-12-20
    Keith R McCrae

    Thrombocytopenia in pregnant women may result from a number of diverse etiologies. While some of these are not associated with adverse pregnancy outcomes, others are associated with substantial maternal and/or neonatal morbidity and mortality. However, specific therapies, if instituted promptly, may significantly improve the outcomes of affected patients and their offspring. Since the clinical features of many of these disorders often overlap, identifying a specific cause of thrombocytopenia in a pregnant patient may be difficult. However, through familiarity with the more common clinical and laboratory features of each of these disorders, accurate diagnosis may be achieved, and appropriate treatment instituted in most cases. In this review, we discuss the differential diagnosis of the more common causes of pregnancy-associated thrombocytopenia, and provide an overview of approaches to hematologic management.

  • Thromboembolic diseases of childhood.
    Blood Rev. (IF 6.125) Pub Date : 2002-12-20
    S Revel-Vilk,P Massicotte

    Over the last decade, pediatric thrombophilia programs have emerged around the world as a new discipline in pediatric hematology. These programs specialize in the diagnosis, prevention and treatment of children with thromboembolic events (TEs) in both the venous and arterial systems. The need for separate pediatric programs has been discussed previously. (J Pediatr Hematol Oncol 1997; 19: 7-22.) The following article will update previous reviews (Hematol Oncol Clin North Am 1998; 12: 1283-1312; Thromb Haemost 1997; 78: 715-725) and will concentrate on three aspects: (1) The risk factors for acquiring TEs; (2) The confirmatory diagnostic tests used in children with TEs; and (3) The different antithrombotic agents used for prevention and treatment. The current knowledge in respect to the above points is only the "tip of the iceberg". Well-designed prospective trials are required to establish the contribution of congenital prothrombotic disorders, appropriate diagnostic strategies, and optimal therapy for children with TEs.

  • The diagnosis and treatment of hairy-cell leukaemia.
    Blood Rev. (IF 6.125) Pub Date : 2002-09-28
    D J Allsup,J C Cawley

    The diagnosis of HCL is usually straightforward and is based on the identification of typical HCs in the blood and bone marrow. The suspected diagnosis is confirmed by a combination of TRAP cytochemistry, a distinctive immunophenotype and characteristic BM trephine appearances. Nucleoside treatment is highly effective in inducing prolonged remissions; relapsing patients can usually be successfully retreated with nucleoside. Monoclonal antibody therapy is a promising novel approach to the treatment of resistant disease.

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上海纽约大学William Glover