Traditionally, primary immune deficiencies have been defined based on increased susceptibility to recurrent and/or severe infections. However, immune dysregulation, manifesting with autoimmunity or hyperinflammatory disease, has emerged as a common feature. This is especially true in patients affected by combined immune deficiency (CID), a group of disorders caused by genetic defects that impair, but do not completely abolish, T-cell function. Hypomorphic mutations in the recombination activating genes RAG1 and RAG2 represent the prototype of the broad spectrum of clinical and immunological phenotypes associated with CID. The study of patients with RAG deficiency and with other forms of CID has revealed distinct abnormalities in central and peripheral T- and B-cell tolerance as the key mechanisms involved in immune dysregulation. Understanding the pathophysiology of autoimmunity and hyperinflammation in these disorders may also permit more targeted therapeutic interventions.

Epstein-Barr virus (EBV) is an enigma; on one hand, it infects and persists in latent form in the vast majority of the global population, causing relatively benign disease in otherwise healthy individuals. On the other hand, EBV represents the first identified oncogenic virus, capable of causing ≥7 different types of malignancies, usually in immunocompromised individuals. Furthermore, some individuals with defined inborn errors of immunity exhibit extreme susceptibility to EBV-induced disease, developing severe and often fatal infectious mononucleosis, hemophagocytic lymphohistiocytosis, lymphoproliferative disease, and/or EBV+ B-cell lymphoma. Thus, host and pathogen have coevolved to enable viral persistence and survival with minimal collateral damage to the healthy host. However, acquired or genetic disruptions to host defense that tip the balance in favor of EBV can have catastrophic effects. The study of primary immunodeficiencies has provided opportunities to define nonredundant requirements for host defense against EBV infection. This has not only revealed mechanisms underlying EBV-induced disease in these primary immunodeficiencies but also identified molecules and pathways that could be targeted to enhance the efficacy of an EBV-specific vaccine or treat severe EBV infection and pathological consequences in immunodeficient hosts.

Viral infections are common and are potentially life-threatening in patients with moderate to severe primary immunodeficiency disorders. Because T-cell immunity contributes to the control of many viral pathogens, adoptive immunotherapy with virus-specific T cells (VSTs) has been a logical and effective way of combating severe viral disease in immunocompromised patients in multiple phase 1 and 2 clinical trials. Common viral targets include cytomegalovirus, Epstein-Barr virus, and adenovirus, though recent published studies have successfully targeted additional pathogens, including HHV6, BK virus, and JC virus. Though most studies have used VSTs derived from allogenic stem cell donors, the use of banked VSTs derived from partially HLA-matched donors has shown efficacy in multicenter settings. Hence, this approach could shorten the time for patients to receive VST therapy thus improving accessibility. In this review, we discuss the usage of VSTs for patients with primary immunodeficiency disorders in clinical trials, as well as future potential targets and methods to broaden the applicability of virus-directed T-cell immunotherapy for this vulnerable patient population.

While we are now able to diagnose inherited thrombophilias in a substantial number of patients with venous thromboembolism (VTE), the initial hope that their presence would inform recurrence risk and thus decisions on anticoagulation duration has largely been disappointing. Indeed, the presence or absence of transient provoking risk factors has proven to be the most important determinant of VTE recurrence risk. Thus, particular attention to transient acquired risk factors for VTE remains paramount, as they have generally been shown to carry more prognostic weight than inherited thrombophilias. The presence of other acquired risk factors may require additional management considerations, whether pertaining to anticoagulant choice, as in antiphospholipid antibody syndrome, or to addressing a new predisposing medical condition, as in malignancy. Antithrombin deficiency or the presence of ≥1 thrombophilic defect may be exceptions that can have a role in prognostication; however, as illustrated in this review through several case vignettes, interpretation and clinical application of the results of inherited thrombophilia testing is nuanced. We have chosen to focus on cases in which patients have been identified as having thrombophilic defects rather than the indications for undertaking testing in the first place or the extent of investigation. Management decisions in such cases ultimately hinge on individualized consideration of the benefits and risks of anticoagulation along with patient preference rather than on an algorithmic pathway based on thrombophilia status.

Venous thrombosis rarely occurs at unusual sites such as cerebral, splanchnic, upper-extremity, renal, ovarian, or retinal veins. Clinical features, symptoms, and risk factors of rare thrombotic manifestations are heterogeneous and in large part differ from those typical of the commonest manifestations of venous thrombosis at the lower extremities. The therapeutic approach also varies widely according to the affected site, whether cerebral, abdominal, or extraabdominal. To date, anticoagulant therapy for thrombosis at unusual sites is generally accepted, but the optimal therapeutic approach remains challenging. This review is focused on the treatment of unusual thrombotic manifestations as reported in the most recent guidelines and according to the updated scientific literature.

The most important decision in the long-term treatment of venous thromboembolism (VTE) is how long to anticoagulate. VTE provoked by a reversible risk factor, or a first unprovoked isolated distal deep vein thrombosis (DVT), generally should be treated for 3 months. VTE provoked by a persistent or progressive risk factor (eg, cancer), or a second unprovoked proximal DVT or PE, is generally treated indefinitely. First unprovoked proximal DVT or PE may be treated for 3 to 6 months or indefinitely. Male sex, presentation as PE (particularly if concomitant proximal DVT), a positive d-dimer test after stopping anticoagulation, an antiphospholipid antibody, low risk of bleeding, and patient preference favor indefinite anticoagulation. The type of indefinite anticoagulation is of secondary importance. Low-dose oral Xa inhibitors are convenient and are thought to have a lower risk of bleeding; they are less suitable if there is a higher risk for recurrence. For cancer-associated VTE, we now prefer full-dose oral Xa inhibitors over low-molecular-weight heparin, with gastrointestinal lesions being a relative contraindication. Graduated compression stockings are not routinely indicated after DVT, but are encouraged if there is persistent leg swelling or if a trial of stockings improves symptoms. Medications have a limited role in the treatment of postthrombotic syndrome. After PE, patients should have clinical surveillance for chronic thromboembolic pulmonary hypertension (CTEPH), with ventilation-perfusion scanning and echocardiography being the initial diagnostic tests if CTEPH is a concern. Patients with CTEPH and other symptomatic patients with extensive residual perfusion defects should be evaluated for endarterectomy, balloon pulmonary angioplasty, or vasodilator therapies.

Venous thromboembolism (VTE) is rare in healthy children, but is an increasing problem in children with underlying medical conditions. Pediatric VTE encompasses a highly heterogenous population, with variation in age, thrombosis location, and underlying medical comorbidities. Evidence from pediatric clinical trials to guide treatment of VTE is lacking so treatment is often extrapolated from adult trials and expert consensus opinion. Aspects unique to children include developmental hemostasis and the major role of central venous access devices. There is an absence of information regarding the optimal target levels of anticoagulation for neonates and infants and lack of suitable drug formulations. Anticoagulants, primarily low-molecular-weight heparin and warfarin, are used to treat children with symptomatic VTE. These drugs have significant limitations, including the need for subcutaneous injections and frequent monitoring. Randomized clinical trials of direct oral anticoagulants in pediatric VTE are ongoing, with results anticipated soon. These trials will provide new evidence and options for therapy that have the potential to improve care. International collaborative registries offer the ability to study outcomes of rare subgroups of pediatric VTE (eg, renal vein thrombosis), and will be important to ultimately guide therapy in a more disease-specific manner.

All patients with venous thromboembolism (VTE) should receive anticoagulant treatment in the absence of absolute contraindications. Initial anticoagulant treatment is crucial for reducing mortality, preventing early recurrences, and improving long-term outcome. Treatment and patient disposition should be tailored to the severity of clinical presentation, to comorbidities, and to the potential to receive appropriate care in the outpatient setting. Direct oral anticoagulants (DOACs) used in fixed doses without laboratory monitoring are the agents of choice for the treatment of acute VTE in the majority of patients. In comparison with conventional anticoagulation (parenteral anticoagulants followed by vitamin K antagonists), these agents showed improved safety (relative risk [RR] of major bleeding, 0.61; 95% confidence interval [CI], 0.45-0.83) with a similar risk of recurrence (RR, 0.90; 95% CI, 0.77-1.06). Vitamin K antagonists or low molecular weight heparins are still alternatives to DOACs for the treatment of VTE in specific patient categories such as those with severe renal failure or antiphospholipid syndrome, or cancer, respectively. In addition to therapeutic anticoagulation, probably less than 10% of patients require reperfusion by thrombolysis or interventional treatments; those patients are hemodynamically unstable with acute pulmonary embolism, and a minority of them have proximal limb-threatening deep vein thrombosis (DVT). The choice of treatment should be driven by the combination of evidence from clinical trials and by local expertise. The majority of patients with acute DVT and a proportion of selected hemodynamically stable patients with acute pulmonary embolism can be safely managed as outpatients.

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cause of vascular death after heart attack and stroke. Anticoagulation therapy is the cornerstone of VTE treatment. Despite such therapy, up to 50% of patients with DVT develop postthrombotic syndrome, and up to 4% of patients with PE develop chronic thromboembolic pulmonary hypertension. Therefore, better therapies are needed. Although direct oral anticoagulants are more convenient and safer than warfarin for VTE treatment, bleeding remains the major side effect, particularly in cancer patients. Factor XII and factor XI have emerged as targets for new anticoagulants that may be safer. To reduce the complications of VTE, attenuation of thrombin activatable fibrinolysis inhibitor activity is under investigation in PE patients to enhance endogenous fibrinolysis, whereas blockade of leukocyte interaction with the vessel wall is being studied to reduce the inflammation that contributes to postthrombotic syndrome in DVT patients. Focusing on these novel antithrombotic strategies, this article explains why safer anticoagulants are needed, provides the rationale for factor XII and XI as targets for such agents, reviews the data on the factor XII- and factor XI-directed anticoagulants under development, describes novel therapies to enhance fibrinolysis and decrease inflammation in PE and DVT patients, respectively, and offers insights into the opportunities for these novel VTE therapies.

CD19-targeted immunotherapies have drastically improved outcomes for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL) patients. Such therapies, including blinatumomab and CD19 chimeric antigen receptor (CD19CAR) T cells, yield high remission rates and can bridge to more definitive consolidation therapy with curative intent. Both treatments are approved by the US Food and Drug Administration (FDA) for r/r ALL (CD19CAR T-cell approval is restricted to patients ≤25 years old). Although availability of blinatumomab and CD19CAR T cells has extended options for the treatment of r/r ALL, prioritizing the sequence of these agents on an individual-patient basis may be difficult for the treating physician. Considering each therapy's advantages, limitations, and challenges is necessary when choosing between them. Although patients may receive both blinatumomab and CD19CAR T cells sequentially in cases that fail to respond or subsequently relapse, a proportion of patients treated with CD19-targeted immunotherapy will lose expression of CD19 and will be excluded from receiving the alternative CD19-targeted therapy. Thus, weighing all considerations for each patient before selecting a CD19-targeted immunotherapy is crucial. Here, we discuss real-life scenarios of adults with r/r ALL, in which we selected either blinatumomab or CD19CAR T-cell therapy, and the rationale behind each decision.

Anemia is a very common comorbidity in patients with heart failure (HF), affecting ∼30% of stable ambulatory patients and 50% patients with acute decompensated HF. Absolute or functional iron deficiency (ID) is seen in ∼50% patients with HF. Both of these comorbidities often coexist and are independently associated with increased mortality and hospitalizations. These findings led several investigators to test the hypotheses that treatment of anemia and ID in HF would improve symptoms and long-term outcomes. Small studies showed that erythropoiesis-stimulating agents (ESAs) improve subjective measures of HF. However, a large pivotal outcome trial found that the ESA darbepoetin alfa did not improve long-term outcomes in patients with HF with reduced ejection fraction and instead was associated with adverse effects. Studies using IV iron have had somewhat greater success, showing improvements in subjective and some objective measures of HF. However, more research is needed to establish the best treatment options for these high-risk patients. We present 5 common scenarios of patients with HF and anemia and describe our personal approach on how we might treat them based on objective evidence where available. An algorithm that offers guidance in regard to personalized therapy for such patients is also presented.

Improved personalized adjustment of primary therapy to the perceived risk of relapse by using new prognostic markers for treatment stratification may be beneficial to patients with acute lymphoblastic leukemia (ALL). Here, we review the advances that have shed light on the role of IKZF1 aberration as prognostic factor in pediatric ALL and summarize emerging concepts in this field. Continued research on the interplay of disease biology with exposure and response to treatment will be key to further improve treatment strategies.

Intensive therapies are often medically indicated for older adults with hematologic malignancies. These may include induction chemotherapy for acute myeloid leukemia (AML), as well as autologous hematopoietic cell transplant (autoHCT) and allogeneic hematopoietic cell transplant (alloHCT). However, it is not always clear how to best deliver these therapies, in terms of determining treatment eligibility, as well as adjusting or adding supportive measures to the treatment plan to maximize successful outcomes. Beyond performance status and presence of comorbidities, comprehensive geriatric assessment and individual geriatric metrics have increasingly been used to prognosticate in these settings and may offer the best approach to personalizing therapy. In the setting of AML induction, evidence supports the use of measures of physical function as independent predictors of survival. For patients undergoing alloHCT, functional status, as measured by instrumental activities of daily living (IADL) and gait speed, may be an important pretransplant assessment. IADL has also been associated with post-autoHCT morbidity and mortality. Current best practice includes assessment of relevant geriatric metrics prior to intensive therapy, and work is ongoing to develop complementary interventions.

Older adults represent the growing majority of patients diagnosed with hematologic disorders, yet they remain underrepresented on clinical trials. Older patients of the same chronologic age differ from one another with varying comorbidity and functional reserve. The concepts of frailty and resilience are important to patient-centered care and are patient and setting specific. The use of geriatric assessment to inform tailored decision making and management can personalize care for older adults with hematologic malignancies. This article will highlight available evidence to support the role of geriatric assessment measures to enhance quality of care for older adults diagnosed with hematologic malignancies.

The clinical development of effective cancer immunotherapies, along with advances in genomic analysis, has led to the identification of tumor environmental features that predict for sensitivity to immune checkpoint blockade therapy (CBT). Early-phase clinical trial results have demonstrated the remarkable effectiveness of CBT in specific lymphoma subtypes, including classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma. Conversely, CBT has been relatively disappointing in follicular lymphoma and diffuse large B-cell lymphoma. These clinical observations, coupled with important scientific discoveries, have uncovered salient features of the lymphoma microenvironment that correlate with immunotherapy response in patients. For example, classical Hodgkin lymphoma is characterized by an inflammatory environment, genetic alterations that facilitate escape from immune attack, and sensitivity to PD-1 blockade therapy. On the other hand, for lymphomas in which measures of immune surveillance are lacking, including follicular lymphoma and most diffuse large B-cell lymphomas, anti-PD-1 therapy has been less effective. An improved understanding of the immune landscapes of these lymphomas is needed to define subsets that might benefit from CBT. In this article, we describe the immune environments associated with major B-cell lymphomas with an emphasis on the immune escape pathways orchestrated by these diseases. We also discuss how oncogenic alterations in lymphoma cells may affect the cellular composition of the immune environment and ultimately, vulnerability to CBT. Finally, we highlight key areas for future investigation, including the need for the development of biomarkers that predict for sensitivity to CBT in lymphoma patients.

Patients with cancer have an increased risk of thromboembolism, which is the second leading cause of death in these patients. Several mechanisms of the prothrombotic state in these patients have been proposed. Among them are a platelet activation receptor, C-type lectin-like receptor 2 (CLEC-2), and its endogenous ligand podoplanin, which are the focus of this review. CLEC-2 is almost specifically expressed in platelets/megakaryocytes in humans. A membrane protein, podoplanin is expressed in certain types of cancer cells, including squamous cell carcinoma, brain tumor, and osteosarcoma, in addition to several normal tissues, including kidney podocytes and lymphatic endothelial cells but not vascular endothelial cells. In the bloodstream, podoplanin induces platelet activation by binding to CLEC-2 and facilitates hematogenous cancer metastasis and cancer-associated thrombosis. In an experimental lung metastasis model, the pharmacological depletion of CLEC-2 from platelets in mice resulted in a marked reduction of lung metastasis of podoplanin-expressing B16F10 cells. Control mice with B16F10 orthotopically inoculated in the back skin showed massive thrombus formation in the lungs, but the cancer-associated thrombus formation in CLEC-2-depleted mice was significantly inhibited, suggesting that CLEC-2-podoplanin interaction stimulates cancer-associated thrombosis. Thromboinflammation induced ectopic podoplanin expression in vascular endothelial cells or macrophages, which may also contribute to cancer-associated thrombosis. CLEC-2 depletion in cancer-bearing mice resulted in not only reduced cancer-associated thrombosis but also reduced levels of plasma inflammatory cytokines, anemia, and sarcopenia, suggesting that cancer-associated thrombosis may cause thromboinflammation and cancer cachexia. Blocking CLEC-2-podoplanin interaction may be a novel therapeutic strategy in patients with podoplanin-expressing cancer.

Immune thrombocytopenia (ITP) is the most common acquired thrombocytopenia after chemotherapy-induced thrombocytopenia. Existing guidelines describe the management and treatment of most patients who, overall, do well, even if they present with chronic disease, and they are usually not at a high risk for bleeding; however, a small percentage of patients is refractory and difficult to manage. Patients classified as refractory have a diagnosis that is not really ITP or have disease that is difficult to manage. ITP is a diagnosis of exclusion; no specific tests exist to confirm the diagnosis. Response to treatment is the only affirmative confirmation of diagnosis. However, refractory patients do not respond to front-line or other treatments; thus, no confirmation of diagnosis exists. The first section of this review carefully evaluates the diagnostic considerations in patients with refractory ITP. The second section describes combination treatment for refractory cases of ITP. The reported combinations are divided into the era before thrombopoietin (TPO) and rituximab and the current era. Current therapy appears to have increased effectiveness. However, the definition of refractory, if it includes insufficient response to TPO agents, describes a group with more severe and difficult-to-treat disease. The biology of refractory ITP is largely unexplored and includes oligoclonality, lymphocyte pumps, and other possibilities. Newer treatments, especially rapamycin, fostamatinib, FcRn, and BTK inhibitors, may be useful components of future therapy given their mechanisms of action; however, TPO agents, notwithstanding failure as monotherapy, appear to be critical components. In summary, refractory ITP is a complicated entity in which a precise specific diagnosis is as important as the development of effective combination treatments.

Common variable immune deficiency (CVID) is one of the most common congenital immune defects encountered in clinical practice. The condition occurs equally in males and females, and most commonly in the 20- to 40-year-old age group. The diagnosis is made by documenting reduced serum concentrations of immunoglobulin G (IgG), IgA, and usually IgM, together with loss of protective antibodies. The genetics of this syndrome are complex and are still being unraveled, but the hallmarks for most patients, as with other immune defects, include acute and chronic infections of the sinopulmonary tract. However, other noninfectious autoimmune or inflammatory conditions may also occur in CVID, and indeed these may be the first and only sign that a significant immune defect is present. These manifestations include episodes of immune thrombocytopenia, autoimmune hemolytic anemia, or neutropenia, in addition to splenomegaly, generalized or worrisome lymphadenopathy, and malignancy, especially lymphoma. These issues commonly bring the patient to the attention of hematologists for both evaluation and treatment. This article discusses 3 cases in which patients with CVID had some of these presenting issues and what hematology input was required.

The management of chronic lymphocytic leukemia (CLL) has undergone dramatic changes over the previous 2 decades with the introduction of multiple new therapies and new combinations. Management of the newly diagnosed asymptomatic patient has not significantly changed outside of the development of a number of prognostic factors and the CLL International Prognostic Index, which is helpful in discussions regarding prognosis and likelihood of requiring treatment. When therapy is required, initial treatment of most patients now includes either the Bruton tyrosine kinase inhibitor ibrutinib or the B-cell lymphoma 2 inhibitor venetoclax in combination with obinutuzumab. Current frontline trials are focused on the optimal sequencing or combination of targeted therapies. In this review, we will discuss the management of previously untreated CLL with an emphasis on the clinical trials that have formed the standard of care, as well as those newer studies that are likely to form the next generation of therapy.

Integrins are a large family of heterodimeric cell surface receptors that bind prototypic ligands on neighboring cells or in the extracellular matrix. Numerous studies have revealed key roles for platelet and leukocyte integrins in adhesion and migration and, thereby, their significance for hemostasis and immunity. The clinical importance of these integrins has also become clear, because aberrant integrin expression and/or behavior are associated with bleeding disorders, immunodeficiency, or autoimmune diseases. Importantly, overwhelming evidence gathered over recent years shows that regulation of integrin function is far more complex than previously assumed; a picture has emerged of multiple cytoplasmic, cell surface, and extracellular regulators working together to ensure cell type-specific and integrin-specific control of integrin functions. Here, we discuss recent insights into the dynamic activation and suppression of hematopoietic integrins, as well as their implications for platelet and leukocyte function in health and disease.