Transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI) are syndromes of acute respiratory distress that occur within 6 hours of blood transfusion. TACO and TRALI are the leading causes of transfusion-related fatalities, and specific therapies are unavailable. Diagnostically, it remains very challenging to distinguish TACO and TRALI from underlying causes of lung injury and/or fluid overload as well as from each other. TACO is characterized by pulmonary hydrostatic (cardiogenic) edema, whereas TRALI presents as pulmonary permeability edema (noncardiogenic). The pathophysiology of both syndromes is complex and incompletely understood. A 2-hit model is generally assumed to underlie TACO and TRALI disease pathology, where the first hit represents the clinical condition of the patient and the second hit is conveyed by the transfusion product. In TACO, cardiac or renal impairment and positive fluid balance appear first hits, whereas suboptimal fluid management or other components in the transfused product may enable the second hit. Remarkably, other factors beyond volume play a role in TACO. In TRALI, the first hit can, for example, be represented by inflammation, whereas the second hit is assumed to be caused by antileukocyte antibodies or biological response modifiers (eg, lipids). In this review, we provide an up-to-date overview of TACO and TRALI regarding clinical definitions, diagnostic strategies, pathophysiological mechanisms, and potential therapies. More research is required to better understand TACO and TRALI pathophysiology, and more biomarker studies are warranted. Collectively, this may result in improved diagnostics and development of therapeutic approaches for these life-threatening transfusion reactions.

Since the 1970s, introduction of serological assays targeting virus-specific antibodies and antigens has been effective in identifying blood donations infected with the classic transfusion-transmitted infectious agents (TTIs; hepatitis B virus [HBV], HIV, human T-cell lymphotropic virus types I and II, hepatitis C virus [HCV]). Subsequently, progressive implementation of nucleic acid-amplification technology (NAT) screening for HIV, HCV, and HBV has reduced the residual risk of infectious-window-period donations, such that per unit risks are <1 in 1 000 000 in the United States, other high-income countries, and in high-incidence regions performing NAT. NAT screening has emerged as the preferred option for detection of newer TTIs including West Nile virus, Zika virus (ZIKV), and Babesia microti Although there is continual need to monitor current risks due to established TTI, ongoing challenges in blood safety relate primarily to surveillance for emerging agents coupled with development of rapid response mechanisms when such agents are identified. Recent progress in development and implementation of pathogen-reduction technologies (PRTs) provide the opportunity for proactive rather than reactive response to blood-safety threats. Risk-based decision-making tools and cost-effectiveness models have proved useful to quantify infectious risks and place new interventions in context. However, as evidenced by the 2015 to 2017 ZIKV pandemic, a level of tolerable risk has yet to be defined in such a way that conflicting factors (eg, theoretical recipient risk, blood availability, cost, and commercial interests) can be reconciled. A unified approach to TTIs is needed, whereby novel tests and PRTs replace, rather than add to, existing interventions, thereby ameliorating cost and logistical burden to blood centers and hospitals.

Blood transfusion is the most common procedure completed during a given hospitalization in the United States. Although often life-saving, transfusions are not risk-free. One sequela that occurs in a subset of red blood cell (RBC) transfusion recipients is the development of alloantibodies. It is estimated that only 30% of induced RBC alloantibodies are detected, given alloantibody induction and evanescence patterns, missed opportunities for alloantibody detection, and record fragmentation. Alloantibodies may be clinically significant in future transfusion scenarios, potentially resulting in acute or delayed hemolytic transfusion reactions or in difficulty locating compatible RBC units for future transfusion. Alloantibodies can also be clinically significant in future pregnancies, potentially resulting in hemolytic disease of the fetus and newborn. A better understanding of factors that impact RBC alloantibody formation may allow general or targeted preventative strategies to be developed. Animal and human studies suggest that blood donor, blood product, and transfusion recipient variables potentially influence which transfusion recipients will become alloimmunized, with genetic as well as innate/adaptive immune factors also playing a role. At present, judicious transfusion of RBCs is the primary strategy invoked in alloimmunization prevention. Other mitigation strategies include matching RBC antigens of blood donors to those of transfusion recipients or providing immunomodulatory therapies prior to blood product exposure in select recipients with a history of life-threatening alloimmunization. Multidisciplinary collaborations between providers with expertise in transfusion medicine, hematology, oncology, transplantation, obstetrics, and immunology, among other areas, are needed to better understand RBC alloimmunization and refine preventative strategies.

Blood transfusions are life-saving therapies; however, they can result in adverse events that can be infectious or, more commonly, noninfectious. The most common noninfectious reactions include febrile nonhemolytic transfusion reactions, allergic transfusion reactions, transfusion-associated circulatory overload, transfusion-related acute lung injury, and acute and delayed hemolytic transfusion reactions. These reactions can be asymptomatic, mild, or potentially fatal. There are several new methodologies to diagnose, treat, and prevent these reactions. Hemovigilance systems for monitoring transfusion events have been developed and demonstrated decreases in some adverse events, such as hemolytic transfusion reactions. Now vein-to-vein databases are being created to study the interactions of the donor, product, and patient factors in the role of adverse outcomes. This article reviews the definition, pathophysiology, management, and mitigation strategies, including the role of the donor, product, and patient, of the most common noninfectious transfusion-associated adverse events. Prevention strategies, such as leukoreduction, plasma reduction, additive solutions, and patient blood management programs, are actively being used to enhance transfusion safety. Understanding the incidence, pathophysiology, and current management strategies will help to create innovative products and continually hone in on best transfusion practices that suit individualized patient needs.

The hematopoietic system produces new blood cells throughout life. Mature blood cells all derived from a pool of rare long-lived hematopoietic stem cells (HSCs) that are mostly quiescent but occasionally divide and self-renew to maintain the stem cell pool and to insure the continuous replenishment of blood cells. Mitochondria have recently emerged as critical not only for HSC differentiation and commitment but also for HSC homeostasis. Mitochondria are dynamic organelles that orchestrate a number of fundamental metabolic and signaling processes, producing most of the cellular energy via oxidative phosphorylation. HSCs have a relatively high amount of mitochondria that are mostly inactive. Here, we review recent advances in our understanding of the role of mitochondria in HSC homeostasis and discuss, among other topics, how mitochondrial dynamism and quality control might be implicated in HSC fate, self-renewal, and regenerative potential.

Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion-based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-trans retinoic acid- and ATO-related toxicities, as well as recommendations for molecular assessment of the response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women. The most important challenges remaining in APL include early death, which still occurs before and during induction therapy, and optimizing treatment in patients with high-risk disease.

Fostamatinib is a spleen tyrosine kinase inhibitor recently approved for the treatment of chronic immune thrombocytopenia (ITP) in patients without adequate response to at least 1 prior line of therapy. This article reviews fostmatinib's mechanism of action and its clinical safety and efficacy in 2 industry-sponsored multicenter phase 3 randomized controlled trials in North America, Australia, and Europe (FIT1 and FIT2). Cost comparisons are discussed as well as the role of fostamatinib in relation to other options for chronic ITP.

Blinatumomab, a bispecific T-cell engager (BiTE) associated with improved survival in relapsed or refractory acute lymphoblastic leukemia (ALL), was recently approved for treatment of minimal residual disease (MRD). MRD is an important predictor of survival in ALL, and recent studies suggest that achievement of MRD-negativity with blinatumomab improves outcomes in patients with ALL. However, further research is needed to determine how to optimally incorporate blinatumomab, and other novel therapies, into current therapies for ALL.

There is a Blood Commentary on this article in this issue.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.

Bone disease is a cardinal complication of multiple myeloma that affects quality of life and survival. Osteocytes have emerged as key players in the development of myeloma-related bone disease. Along with other factors, they participate in increased osteoclast activity, decreased osteoblast function, and immunosuppressed marrow microenvironment, which deregulate bone turnover and result in bone loss and skeletal-related events. Denosumab is a novel alternative to bisphosphonates against myeloma bone disease. Special considerations in this constantly evolving field are thoroughly discussed.

The classical model of hematopoiesis proposes a hierarchy in which a small number of multipotent hematopoietic stem cells (HSCs) maintain all blood lineages by giving rise to progeny that pass through discrete progenitor stages. At each stage, lineage differentiation potential is restricted, coupled with the loss of ability to self-renew. Recently, single-cell approaches have been used to test certain assumptions made by this model, in particular relating to megakaryocyte (Mk) and erythroid (E) development. An alternative model has emerged in which substantial heterogeneity and lineage-priming exists within the HSC compartment, including the existence of multipotent but megakaryocyte/platelet-biased HSCs. Hematopoietic differentiation follows a hierarchical continuum, passing through cellular nodes and branch points. Megakaryocytes are produced via a shared pathway with the erythroid lineage, also shared in its early stages with mast cells, eosinophils, and basophils, but separate from other myeloid and lymphoid lineages. In addition, distinct pathways for direct differentiation of Mk from HSCs may coexist and could be important in situations of increased physiological requirements or in malignancies. Further work at single-cell resolution using multiomic approaches and examining Mk-E biased subsets within their physiological context will undoubtedly improve our understanding of normal hematopoiesis and ability to manipulate this in pathology.

Single-cell transcriptomics has recently emerged as a powerful tool to analyze cellular heterogeneity, discover new cell types, and infer putative differentiation routes. The technique has been rapidly embraced by the hematopoiesis research community, and like other technologies before, single-cell molecular profiling is widely expected to make important contributions to our understanding of the hematopoietic hierarchy. Much of this new interpretation relies on inference of the transcriptomic landscape as a representation of existing cellular states and associated transitions among them. Here we review how this model allows, under certain assumptions, charting of time-resolved differentiation trajectories with unparalleled resolution and how the landscape of multipotent cells may be rather devoid of discrete structures, challenging our preconceptions about stem and progenitor cell types and their organization. Finally, we highlight how promising technological advances may convert static differentiation landscapes into a dynamic cell flux model and thus provide a more holistic understanding of normal hematopoiesis and blood disorders.

Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing-based assays have shown great promise in allowing multi-"omic" characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

We now have the potential to undertake detailed analysis of the inner workings of thousands of cancer cells, one cell at a time, through the emergence of a range of techniques that probe the genome, transcriptome, and proteome combined with the development of bioinformatics pipelines that enable their interpretation. This provides an unprecedented opportunity to better understand the heterogeneity of chronic lymphocytic leukemia and how mutations, activation states, and protein expression at the single-cell level have an impact on disease course, response to treatment, and outcomes. Herein, we review the emerging application of these new techniques to chronic lymphocytic leukemia and examine the insights already attained through this transformative technology.

Cells and the molecular processes underlying their behavior are highly dynamic. Understanding these dynamic biological processes requires noninvasive continuous quantitative single-cell observations, instead of population-based average or single-cell snapshot analysis. Ideally, single-cell dynamics are measured long-term in vivo; however, despite progress in recent years, technical limitations still prevent such studies. On the other hand, in vitro studies have proven to be useful for answering long-standing questions. Although technically still demanding, long-term single-cell imaging and tracking in vitro have become valuable tools to elucidate dynamic molecular processes and mechanisms, especially in rare and heterogeneous populations. Here, we review how continuous quantitative single-cell imaging of hematopoietic cells has been used to solve decades-long controversies. Because aberrant cell fate decisions are at the heart of tissue degeneration and disease, we argue that studying their molecular dynamics using quantitative single-cell imaging will also improve our understanding of these processes and lead to new strategies for therapies.

Follicular lymphoma (FL) is the most frequently occurring indolent non-Hodgkin lymphoma, with generally favorable outcomes but a variable clinical course. Recent studies have elucidated the consistent and reproducible frequency of early disease progression in FL, occurring in ∼20% of patients. Relapse of FL within 24 months of chemoimmunotherapy (POD24) is now established as a robust marker of poor survival, leading to increased risk of death. Currently, there is no established method of identifying patients at risk for early disease progression at the time of their FL diagnosis. However, numerous studies worldwide are investigating clinical, pathologic, and radiographic biomarkers to help predict POD24, thereby improving subsequent outcomes and adapting therapy based on individual risk. There is also a paucity of standardized treatments for patients with POD24, but investigations are ongoing testing novel targeted therapies and autologous stem cell transplantation strategies. This review provides an overview of early-relapsing FL and our approach to patient management based on recent available data.

Approximately 35% to 50% of patients otherwise cured of hematologic malignancies after allogeneic hematopoietic stem cell transplantation will develop the pleomorphic autoimmune-like syndrome known as chronic graft-versus-host disease (cGVHD). Since in 2005, National Institutes of Health (NIH) consensus panels have proposed definitions and classifications of disease to standardize treatment trials. Recently, the first agent was approved by the US Food and Drug Administration for steroid-refractory cGVHD. Despite these advances, most individuals do not achieve durable resolution of disease activity with initial treatment. Moreover, standardized recommendations on how to best implement existing and novel immunomodulatory agents and taper salvage agents are often lacking. Given the potential life-threatening nature of cGVHD, we employ in our practice patient assessment templates at each clinic visit to elucidate known prognostic indicators and red flags. We find NIH scoring templates practical for ongoing assessments of these complex patient cases and determination of when changes in immunosuppressive therapy are warranted. Patients not eligible or suitable for clinical trials have systemic and organ-directed adjunctive treatments crafted in a multidisciplinary clinic. Herein, we review these treatment options and offer a management and monitoring scaffold for representative patients with cGVHD not responding to initial therapy.

Juvenile myelomonocytic leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood. It is classified as an overlap myeloproliferative/myelodysplastic neoplasm by the World Health Organization and shares some features with chronic myelomonocytic leukemia in adults. JMML pathobiology is characterized by constitutive activation of the Ras signal transduction pathway. About 90% of patients harbor molecular alterations in 1 of 5 genes (PTPN11, NRAS, KRAS, NF1, or CBL), which define genetically and clinically distinct subtypes. Three of these subtypes, PTPN11-, NRAS-, and KRAS-mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in nonsyndromic children, whereas 2 subtypes, JMML in neurofibromatosis type 1 and JMML in children with CBL syndrome, are defined by germline Ras disease and acquired biallelic inactivation of the respective genes in hematopoietic cells. The clinical course of the disease varies widely and can in part be predicted by age, level of hemoglobin F, and platelet count. The majority of children require allogeneic hematopoietic stem cell transplantation for long-term leukemia-free survival, but the disease will eventually resolve spontaneously in ∼15% of patients, rendering the prospective identification of these cases a clinical necessity. Most recently, genome-wide DNA methylation profiles identified distinct methylation signatures correlating with clinical and genetic features and highly predictive for outcome. Understanding the genomic and epigenomic basis of JMML will not only greatly improve precise decision making but also be fundamental for drug development and future collaborative trials.