Burkitt lymphoma (BL) is a highly aggressive, B-cell, non-Hodgkin lymphoma categorized into endemic, sporadic, and immunodeficiency-associated subtypes. BL has distinct pathologic and clinical features, characterized by rapidly progressive tumors with high rates of extranodal involvement. Next-generation-sequencing analyses have further characterized the genomic landscape of BL and our understanding of disease pathogenesis, although these findings have yet to influence treatment. Although most patients are cured with intensive combination chemotherapy, given the paucity of randomized trials, optimal therapy has not been defined. Furthermore, treatment of elderly patients, patients with central nervous system involvement, or those with relapsed disease remains an unmet need. In this review, we highlight the clinical, pathologic, and genomic features, as well as standard and emerging treatment options for adult patients with BL.

Hereditary hemorrhagic telangiectasia (HHT) management is evolving because of the emergence and development of antiangiogenic therapies to eliminate bleeding telangiectasias and achieve hemostasis. This progress is reflected in recent clinical recommendations published in the Second International Guidelines for the Diagnosis and Treatment of HHT, in which systemic therapies including antiangiogenics and antifibrinolytics are now recommended as standard treatment options for bleeding. This review highlights the new recommendations especially relevant to hematologists in managing bleeding, anticoagulation, and anemia in patients with HHT.

Outcomes for patients with hematologic malignancy infected with COVID-19 have not been aggregated. The objective of this study was to perform a systematic review and meta-analysis to estimate the risk of death and other important outcomes for these patients. We searched PubMed and EMBASE up to 20 August 2020 to identify reports of patients with hematologic malignancy and COVID-19. The primary outcome was a pooled mortality estimate, considering all patients and only hospitalized patients. Secondary outcomes included risk of intensive care unit admission and ventilation in hospitalized patients. Subgroup analyses included mortality stratified by age, treatment status, and malignancy subtype. Pooled prevalence, risk ratios (RRs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Thirty-four adult and 5 pediatric studies (3377 patients) from Asia, Europe, and North America were included (14 of 34 adult studies included only hospitalized patients). Risk of death among adult patients was 34% (95% CI, 28-39; N = 3240) in this sample of predominantly hospitalized patients. Patients aged ≥60 years had a significantly higher risk of death than patients <60 years (RR, 1.82; 95% CI, 1.45-2.27; N = 1169). The risk of death in pediatric patients was 4% (95% CI, 1-9; N = 102). RR of death comparing patients with recent systemic anticancer therapy to no treatment was 1.17 (95% CI, 0.83-1.64; N = 736). Adult patients with hematologic malignancy and COVID-19, especially hospitalized patients, have a high risk of dying. Patients ≥60 years have significantly higher mortality; pediatric patients appear to be relatively spared. Recent cancer treatment does not appear to significantly increase the risk of death.

Although therapeutic strategies have been adapted to age and comorbidities for a long time, almost all multiple myeloma (MM) patients currently receive similar treatment, whatever their disease risk category. However, high-risk MM patients still constitute an unmet medical need and should benefit from the most efficient drug combinations. Herein, we review and discuss how to optimally define risk and why a revision of the current definition is urgently needed.

Treatment of splanchnic vein thrombosis (SVT) is challenging, and evidence to guide therapeutic decisions remains scarce. The objective of this systematic review and meta-analysis was to determine the efficacy and safety of anticoagulant therapy for SVT. MEDLINE, EMBASE, and clinicaltrials.gov were searched from inception through December 2019, without language restrictions, to include observational studies and randomized controlled trials reporting radiological or clinical outcomes in patients with SVT. Pooled proportions and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated in a random-effects model. Of 4312 records identified by the search, 97 studies including 7969 patients were analyzed. In patients receiving anticoagulation, the rates of SVT recanalization, SVT progression, recurrent venous thromboembolism (VTE), major bleeding, and overall mortality were 58% (95% CI, 51-64), 5% (95% CI, 3-7), 11% (95% CI, 8-15), 9% (95% CI, 7-12), and 11% (95% CI, 9-14), respectively. The corresponding values in patients without anticoagulation were 22% (95% CI, 15-31), 15% (95% CI, 8-27), 14% (95% CI, 9-21), 16% (95% CI, 13-20), and 25% (95% CI, 20-31). Compared with no treatment, anticoagulant therapy obtained higher recanalization (RR, 2.39; 95% CI, 1.66-3.44) and lower thrombosis progression (RR, 0.24; 95% CI, 0.13-0.42), major bleeding (RR, 0.73; 95% CI, 0.58-0.92), and overall mortality (RR, 0.45; 95% CI, 0.33-0.60). These results demonstrate that anticoagulant therapy improves SVT recanalization and reduces the risk of thrombosis progression without increasing major bleeding. The incidence of recurrent VTE remained substantial in patients receiving anticoagulation, as well. Effects were consistent across the different subgroups of patients. This trial was registered on the PROPERO database at (https://www.crd.york.ac.uk/prospero//display_record.php?ID=CRD42019127870) as #CRD42019127870.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity with distinct pathologic and clinical characteristics. Unlike the malignant cells in classical Hodgkin lymphoma, the disease-defining lymphocyte-predominant cells in NLPHL are consistently positive for CD20, but do not express CD30. The clinical course of NLPHL is indolent in the majority of cases. Most patients present with early-stage disease at the initial diagnosis. First-line treatment of stage IA NLPHL usually consists of limited-field radiotherapy alone. Patients with early-stage NLPHL other than stage IA and intermediate-stage disease mostly receive combined-modality treatment, whereas individuals with advanced NLPHL are treated with chemotherapy alone. In relapsed NLPHL, conventional chemotherapy, anti-CD20 antibodies, and radiotherapy represent active treatment modalities. Only patients with poor-risk characteristics such as early disease recurrence are candidates for aggressive salvage treatment with high-dose chemotherapy and autologous stem cell transplantation. The overall and relative survival of patients with NLPHL is excellent as indicated by a low excess mortality compared with the general population. This article discusses treatment options for patients with NLPHL and factors that influence the choice of therapy on the basis of the available data and 2 clinical cases.

Fetal hemoglobin (HbF) can blunt the pathophysiology, temper the clinical course, and offer prospects for curative therapy of sickle cell disease. This review focuses on (1) HbF quantitative trait loci and the geography of β-globin gene haplotypes, especially those found in the Middle East; (2) how HbF might differentially impact the pathophysiology and many subphenotypes of sickle cell disease; (3) clinical implications of person-to-person variation in the distribution of HbF among HbF-containing erythrocytes; and (4) reactivation of HbF gene expression using both pharmacologic and cell-based therapeutic approaches. A confluence of detailed understanding of the molecular basis of HbF gene expression, coupled with the ability to precisely target by genomic editing most areas of the genome, is producing important preliminary therapeutic results that could provide new options for cell-based therapeutics with curative intent.

Numerous studies have reported significant associations between ABO blood group and risk of cardiovascular disease. These studies have consistently demonstrated that thrombotic risk is significantly reduced in individuals in blood group O. Nevertheless, the biological mechanisms through which ABO influences hemostasis have remained poorly understood. Exciting recent data have provided novel insights into how these ABO effects are modulated and have highlighted that ABO group significantly influences platelet plug formation at sites of vascular injury (primary hemostasis). In particular, ABO affects multiple aspects of von Willebrand factor (VWF) biology. In keeping with their reduced thrombotic risk, plasma VWF levels are ∼25% lower in healthy group O compared with healthy group non-O individuals. In addition, blood group O VWF demonstrates enhanced susceptibility to ADAMTS13 proteolysis. Finally, preliminary findings suggest that the interaction of group O VWF with platelets may also be reduced. Although the molecular mechanisms underlying these ABO effects on VWF have not been fully elucidated, it seems likely that they are mediated in large part by the ABO(H) carbohydrate structures that are carried on both the N- and O-linked glycans of VWF. Interestingly, ABO(H) determinants are also expressed on several different platelet surface glycoprotein receptors. Recent studies support the hypothesis that ABO group not only exerts major quantitative and qualitative effects on VWF, but also affect specific aspects of platelet function. Given the severe morbidity and the mortality associated with thrombotic disorders, defining the mechanisms underlying these ABO effects is not only of scientific interest, but also of direct clinical importance.

Nucleoporin 98 (NUP98) fusion oncoproteins are observed in a spectrum of hematologic malignancies, particularly pediatric leukemias with poor patient outcomes. Although wild-type full-length NUP98 is a member of the nuclear pore complex, the chromosomal translocations leading to NUP98 gene fusions involve the intrinsically disordered and N-terminal region of NUP98 with over 30 partner genes. Fusion partners include several genes bearing homeodomains or having known roles in transcriptional or epigenetic regulation. Based on data in both experimental models and patient samples, NUP98 fusion oncoprotein-driven leukemogenesis is mediated by changes in chromatin structure and gene expression. Multiple cofactors associate with NUP98 fusion oncoproteins to mediate transcriptional changes possibly via phase separation, in a manner likely dependent on the fusion partner. NUP98 gene fusions co-occur with a set of additional mutations, including FLT3-internal tandem duplication and other events contributing to increased proliferation. To improve the currently dire outcomes for patients with NUP98-rearranged malignancies, therapeutic strategies have been considered that target transcriptional and epigenetic machinery, cooperating alterations, and signaling or cell-cycle pathways. With the development of more faithful experimental systems and continued study, we anticipate great strides in our understanding of the molecular mechanisms and therapeutic vulnerabilities at play in NUP98-rearranged models. Taken together, these studies should lead to improved clinical outcomes for NUP98-rearranged leukemia.

Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic stem cell transplantation. Only half of patients with severe acute GVHD respond to first-line treatment with corticosteroids and, for several decades, there was no optimal second-line treatment of patients with corticosteroid-refractory acute GVHD. Ruxolitinib was recently approved for the treatment of corticosteroid-refractory acute GVHD in adult and pediatric patients 12 years and older. Thus, it is important to define the patient population that would now be considered as refractory to ruxolitinib vs ruxolitinib dependent. Here, we propose to define ruxolitinib-refractory acute GVHD as disease that shows: (1) progression of GVHD compared with baseline after at least 5 to 10 days of treatment with ruxolitinib, based either on objective increase in stage/grade, or new organ involvement; (2) lack of improvement in GVHD (partial response or better) compared with baseline after ≥14 days of treatment with ruxolitinib; or (3) loss of response, defined as objective worsening of GVHD determined by increase in stage, grade, or new organ involvement at any time after initial improvement. GVHD manifestations that persist without improvement in patients who had a grade ≥3 treatment-emergent and ruxolitinib-attributed adverse event that did not resolve within 7 days of discontinuing ruxolitinib would serve as a clinical indication for additional treatment. In addition, absence of complete response or very good partial response at day 28 after ruxolitinib could be considered as an eligibility criterion.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare T-cell neoplasm that most commonly arises from a small subset of γ/δ T-cell receptor-expressing lymphocytes. HSTCL is more common in adolescent and young adults and has a rapidly progressive clinical course and poor outcome due to its refractoriness to conventional chemotherapy regimens. Approximately 20% of the cases arise in the background of chronic immunosuppression or immune dysregulation. Patients commonly present with constitutional symptoms, hepatic and liver enlargement, and cytopenias; hematophagocytic syndrome can also occur. The most frequent chromosomal aberrations associated with HSTCL are isochromosome 7q and trisomy 8, and most cases harbor mutations in genes involved in chromatin modification or the JAK/STAT pathway. The rarity of this disease, along with lack of nodal involvement and presenting symptoms that mimic different entities including infectious etiologies, makes this lymphoma a significant diagnostic challenge. In this review, we highlight the clinical and pathologic features of HSTCL. Moreover, we summarize the results of recent molecular studies suggesting potential targets for novel therapeutics strategies.

The discovery of clonal hematopoiesis (CH) in older individuals has changed the way hematologists and stem cell biologists view aging. Somatic mutations accumulate in stem cells over time. While most mutations have no impact, some result in subtle functional differences that ultimately manifest in distinct stem cell behaviors. With a large pool of stem cells and many decades to compete, some of these differences confer advantages under specific contexts. Approximately 20 genes are recurrently found as mutated in CH, indicating they confer some advantage. The impact of these mutations has begun to be analyzed at a molecular level by modeling in cell lines and in mice. Mutations in epigenetic regulators such as DNMT3A and TET2 confer an advantage by enhancing self-renewal of stem and progenitor cells and inhibiting their differentiation. Mutations in other genes involved in the DNA damage response may simply enhance cell survival. Here, we review proposed mechanisms that lead to CH, specifically in the context of stem cell biology, based on our current understanding of the function of some of the CH-associated genes.

Clonal hematopoiesis (CH) is common in older persons and is associated with an increased risk of hematologic cancer. Here, we review studies establishing an association between CH and hematopoietic malignancy, discuss features of CH that are predictive of leukemic progression, and explore the role of hematopoietic stressors in the evolution of CH to acute myeloid leukemia or myelodysplastic syndrome. CH due to point mutations or structural variants such as copy-number alterations is associated with an ∼10-fold increased risk of hematopoietic malignancy. Although the absolute risk of hematopoietic malignancy is low, certain features of CH may confer a higher risk of transformation, including the presence of TP53 or spliceosome gene mutations, a variant allele fraction >10%, the presence of multiple mutations, and altered red blood indices. CH in the setting of peripheral blood cytopenias carries a very high risk of progression to a myeloid malignancy and merits close observation. There is emerging evidence suggesting that hematopoietic stressors contribute to both the development of CH and progression to hematopoietic malignancy. Specifically, there is evidence that genotoxic stress from chemotherapy or radiation therapy, ribosome biogenesis stress, and possibly inflammation may increase the risk of transformation from CH to a myeloid malignancy. Models that incorporate features of CH along with an assessment of hematopoietic stressors may eventually help predict and prevent the development of hematopoietic malignancies.

Acquired genetic mutations in hematopoietic stem or progenitor cells can lead to clonal expansion and imbalanced blood cell production. Clonal hematopoiesis is exceptionally common with human aging, confers a risk of evolution to overt hematologic malignancy, and increases all-cause mortality and the risk of cardiovascular disease. The degree of risk depends on the specific mutant allele driving clonal expansion, number of mutations, mutant allele burden, and concomitant nongenetic risk factors (eg, hypertension or cigarette smoking). People with clonal hematopoiesis may come to clinical attention in a variety of ways, including during the evaluation of a possible hematologic malignancy, as an incidental discovery during molecular analysis of a nonhematologic neoplasm, after hematopoietic cell transplantation, or as a result of germline testing for inherited variants. Even though the risk of clonal progression or a cardiovascular event in an individual patient with clonal hematopoiesis may be low, the possibility of future clinical consequences may contribute to uncertainty and worry, because it is not yet known how to modify these risks. This review summarizes clinical considerations for patients with clonal hematopoiesis, including important points for hematologists to consider discussing with affected persons who may understandably be anxious about having a mutation in their blood that predisposes them to develop a malignancy, but which is significantly more likely to result in a myocardial infarction or stroke. The increasing frequency with which people with clonal hematopoiesis are discovered and the need for counseling these patients is driving many institutions to create specialized clinics. We describe our own experience with forming such clinics.

Clonal expansions of mutated hematopoietic cells, termed clonal hematopoiesis, are common in aging humans. One expected consequence of mutation-associated clonal hematopoiesis is an increased risk of hematologic cancers, which has now been shown in several studies. However, the hematopoietic stem cells that acquire these somatic mutations also give rise to mutated immune effector cells, such as monocytes, granulocytes, and lymphocytes. These effector cells can potentially influence many disease states, especially those with a chronic inflammatory component. Indeed, several studies have now shown that clonal hematopoiesis associates with increased risk of atherosclerotic cardiovascular disease. Emerging data also associate clonal hematopoiesis with other nonhematologic diseases. Here, we will review recent studies linking clonal hematopoiesis to altered immune function, inflammation, and nonmalignant diseases of aging.

Inherited bone marrow failure syndromes (IBMFSs) are characterized by ineffective hematopoiesis and increased risk for developing myeloid malignancy. The pathophysiologies of different IBMFSs are variable and can relate to defects in diverse biological processes, including DNA damage repair (Fanconi anemia), telomere maintenance (dyskeratosis congenita), and ribosome biogenesis (Diamond-Blackfan anemia, Shwachman-Diamond syndrome). Somatic mutations leading to clonal hematopoiesis have been described in IBMFSs, but the distinct mechanisms by which mutations drive clonal advantage in each disease and their associations with leukemia risk are not well understood. Clinical observations and laboratory models of IBMFSs suggest that the germline deficiencies establish a qualitatively impaired functional state at baseline. In this context, somatic alterations can promote clonal hematopoiesis by improving the competitive fitness of specific hematopoietic stem cell clones. Some somatic alterations relieve baseline fitness constraints by normalizing the underlying germline deficit through direct reversion or indirect compensation, whereas others do so by subverting senescence or tumor-suppressor pathways. Clones with normalizing somatic mutations may have limited transformation potential that is due to retention of functionally intact fitness-sensing and tumor-suppressor pathways, whereas those with mutations that impair cellular elimination may have increased risk for malignant transformation that is due to subversion of tumor-suppressor pathways. Because clonal hematopoiesis is not deterministic of malignant transformation, rational surveillance strategies will depend on the ability to prospectively identify specific clones with increased leukemic potential. We describe a framework by which an understanding of the processes that promote clonal hematopoiesis in IBMFSs may inform clinical surveillance strategies.

The treatment of multiple myeloma (MM) is currently being redefined by humoral and cellular immunotherapies. For decades, there was limited belief in immune-based anti-MM therapy as a result of the moderate graft-versus-myeloma effect of allogeneic stem cell transplantation. Today, monoclonal antibodies comprise the new backbone of anti-MM therapy, and T-cell therapies targeting BCMA are emerging as the most potent single agents for MM treatment. Herein, we present our assessment of and vision for MM immunotherapy in the short and midterm.

Vitamin C serves as a cofactor for Fe(II) and 2-oxoglutarate-dependent dioxygenases including TET family enzymes, which catalyze the oxidation of 5-methylcytosine into 5-hydroxymethylcytosine and further oxidize methylcytosines. Loss-of-function mutations in epigenetic regulators such as TET genes are prevalent in hematopoietic malignancies. Vitamin C deficiency is frequently observed in cancer patients. In this review, we discuss the role of vitamin C and TET proteins in cancer, with a focus on hematopoietic malignancies, T regulatory cells, and other immune system cells.

Diamond-Blackfan anemia (DBA) was the first ribosomopathy described and is a constitutional inherited bone marrow failure syndrome. Erythroblastopenia is the major characteristic of the disease, which is a model for ribosomal diseases, related to a heterozygous allelic variation in 1 of the 20 ribosomal protein genes of either the small or large ribosomal subunit. The salient feature of classical DBA is a defect in ribosomal RNA maturation that generates nucleolar stress, leading to stabilization of p53 and activation of its targets, resulting in cell-cycle arrest and apoptosis. Although activation of p53 may not explain all aspects of DBA erythroid tropism, involvement of GATA1/HSP70 and globin/heme imbalance, with an excess of the toxic free heme leading to reactive oxygen species production, account for defective erythropoiesis in DBA. Despite significant progress in defining the molecular basis of DBA and increased understanding of the mechanistic basis for DBA pathophysiology, progress in developing new therapeutic options has been limited. However, recent advances in gene therapy, better outcomes with stem cell transplantation, and discoveries of putative new drugs through systematic drug screening using large chemical libraries provide hope for improvement.

The mature red blood cell (RBC) lacks a nucleus and organelles characteristic of most cells, but it is elegantly structured to perform the essential function of delivering oxygen and removing carbon dioxide from all other cells while enduring the shear stress imposed by navigating small vessels and sinusoids. Over the past several decades, the efforts of biochemists, cell and molecular biologists, and hematologists have provided an appreciation of the complexity of RBC membrane structure, while studies of the RBC membrane disorders have offered valuable insights into structure-function relationships. Within the last decade, advances in genetic testing and its increased availability have made it possible to substantially build upon this foundational knowledge. Although disorders of the RBC membrane due to altered structural organization or altered transport function are heterogeneous, they often present with common clinical findings of hemolytic anemia. However, they may require substantially different management depending on the underlying pathophysiology. Accurate diagnosis is essential to avoid emergence of complications or inappropriate interventions. We propose an algorithm for laboratory evaluation of patients presenting with symptoms and signs of hemolytic anemia with a focus on RBC membrane disorders. Here, we review the genotypic and phenotypic variability of the RBC membrane disorders in order to raise the index of suspicion and highlight the need for correct and timely diagnosis.