Sufficient levels of fetal hemoglobin (HbF) can ameliorate the pathophysiologic basis of sickle cell disease and β-thalassemia postnatally. DNA methylation has long been posited to mediate silencing of HbF expression, but this has been controversial. Recent publications provide definitive evidence for the critical role of HBG gene promoter methylation in silencing and insight into the mechanisms involved. The data support a model in which methylation of CpG sites in the HBG promoters and repressive transcription factors recruit the MBD2-NuRD chromatin remodeling complex, which enforces silencing. These findings have implications for the treatment of β-globin disorders.

In 2014, the International Myeloma Working Group (IMWG) expanded multiple myeloma diagnostic criteria to include a serum free light chain (sFLC) ratio of ≥100 as a standalone myeloma-defining biomarker, based on studies suggesting ∼80% risk of progression to overt myeloma at 2 years. However, subsequent studies demonstrate a substantially lower risk of progression, with population-based registry data showing a 2-year risk as low as 30.4% in this group. Importantly, subsequent data showed that >70% of patients with an sFLC ratio ≥100 have 24-hour monoclonal proteinuria <200 mg, a subgroup with particularly low progression risk (13.5% at 2 years) and minimal risk of irreversible renal failure. Furthermore, with the IMWG diagnostic amendment, an sFLC ratio ≥100 is currently included within the composite end point of progression-free survival in early-intervention clinical trials of high-risk smoldering multiple myeloma (SMM), which poses a risk of misclassifying biochemical changes as clinically meaningful events. We propose immediate revision of the diagnostic criteria to remove sFLC ratio ≥100 as a standalone myeloma-defining event and exclusion of patients with an sFLC ratio ≥100 from trials of newly diagnosed myeloma. These patients should be included in prospective studies on therapeutic interventions in high-risk SMM as well as active surveillance with modern imaging to define their natural history in the contemporary era.

Janus kinase (JAK) inhibitors have changed the treatment landscape of myeloproliferative neoplasms (MPNs), graft-versus-host disease, and several autoimmune conditions. Although approved JAK inhibitors generally target the JAK2 kinase domain, and several also target the JAK1 kinase domain in active form (type I inhibition), new inhibitors that either exhibit a type II mechanism of inhibition of the kinase domain in an inactive state or that target the pseudokinase domain with potential preference or specificity for the JAK2 V617F mutant have progressed to clinical trials. This is the most prevalent mutation in MPNs. An ideal inhibitor would target persistently activated JAK2 in MPNs, eradicate the clone or induce deep molecular remission in addition to clinical and hematologic remission, and spare wild-type JAK2 that is critical for hematopoiesis and immune response. We discuss perspectives of these and other modes of JAK inhibition, as well as primary and secondary/exploratory study end points in clinical trial design, along with potential biomarker correlates to evaluate the potential efficacy of next-generation vs conventional JAK inhibitors.

Chronic active Epstein-Barr virus (EBV; CAEBV) disease is an uncommon, often lethal T and/or natural killer (T/NK)-cell lymphoproliferative disorder that remains underrecognized outside Asia. Recent advances in molecular and immunopathologic studies, together with the 2022 International Consensus Classification and the fifth World Health Organization lymphoma classification, have consolidated the disease concept and diagnostic framework. Recent studies support a model in which mutated EBV infects hematopoietic stem or lymphoid progenitor cells in the bone marrow, establishing latent infection that persists as these progenitors differentiate into T/NK cells. The infected lymphocytes subsequently undergo clonal expansion, immune evasion, and progressive accumulation of genetic and epigenetic alterations, giving rise to systemic CAEBV disease and, in some cases, transformation into EBV-positive lymphomas or leukemias. We review the clinical spectrum and differential diagnosis in relation to EBV-associated hemophagocytic lymphohistiocytosis and EBV-positive lymphomas or leukemias and highlight geographic differences between Asian and non-Asian cohorts. Despite progress, diagnosis remains hampered by the lack of standardized and commercially available assays to identify infected cell subsets. Hematopoietic stem cell transplantation remains the only curative option; however, transplant-related mortality, relapse, and suboptimal outcomes in adult-onset disease underscore the need for optimized conditioning and pretransplant disease control. We review emerging therapeutic strategies, including programmed cell death 1 blockade, JAK inhibition, and EBV-specific cytotoxic T-lymphocyte therapy, and outline priorities for prospective international trials. This review aims to raise global awareness among hematologists and foster collaborative studies to improve outcomes for patients with CAEBV disease.

Pediatric hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome, characterized by heightened T-cell activation and overwhelming interferon gamma production. Rather than a binary "primary" vs "secondary" framework, it is best conceptualized as a threshold phenomenon that occurs when combined genetic and environmental factors exceed a critical tipping point, leading to a recognizable clinical pattern of abnormal immunopathology. In addition to classic genetic cytotoxic defects, an increasing number of genetic lesions continue to be recognized as related to HLH. Environmental triggers frequently include malignancy, infection, and rheumatologic disorders, and identifying underlying factors driving HLH is a crucial component of evaluation. The revised HLH-2004 criteria are an important tool in promptly recognizing HLH, but clinical criteria may be fulfilled by other inflammatory disorders. Genetic and functional immune testing are complementary tools for diagnosis and establishing recurrence risk. Dexamethasone and etoposide remain cornerstones of initial therapy but are best used in an individualized, response-based manner with close monitoring of inflammatory markers. Newer, more targeted agents continue to emerge and are often critical additions for achieving disease control. Most patients with inherited cytotoxic defects and other select causes require hematopoietic cell transplant for cure, which should occur as soon as feasible once adequate, not perfect, HLH control is established to minimize risk of reactivation, infection, and toxicity. This review aims to highlight key advancements in defining, diagnosing, and treating HLH based on a growing understanding of HLH pathophysiology. We also provide perspectives on practical clinical approaches that may be useful for diagnosing and treating pediatric HLH.

The use of posttransplant cyclophosphamide was initially pioneered as a means of permitting haploidentical transplantation across HLA barriers. This approach has now become a standard of care for the prevention of significant acute and chronic graft-versus-host disease (GVHD) after related and unrelated HLA-matched allogeneic peripheral blood stem cell transplant across a full spectrum of conditioning intensities. This article discusses recent advances, the mechanisms of action, and important unresolved questions in the prevention of GVHD that will help inform new prospective clinical studies.

Measurable residual disease (MRD) monitoring has become a critical component in the management of acute myeloid leukemia (AML), to inform prognosis, guide therapy, and serve as a key end point in clinical trials. The 2025 update of the MRD guideline provides a comprehensive and refined framework for MRD assessment, aligned with the European LeukemiaNet (ELN) 2022 genetic risk classification. Developed by members of the ELN AML MRD Working Party, the guidelines incorporate expert consensus determined through a 2-stage Delphi round. They address the clinical implementation of MRD methodologies, technical considerations, integration into clinical trials, and future directions. Importantly, MRD recommendations are tailored to individual prognostic and genetic subgroups. A new qualitative MRD response category, designated as optimal, warning, or high risk of treatment failure, has been introduced to facilitate contextual interpretation of the MRD burden and its clinical relevance. Notably, ultrahigh-sensitivity next-generation sequencing-based MRD assessment is now recommended for FLT3 internal tandem duplication-mutated AML after intensive chemotherapy and before allogeneic hematopoietic cell transplantation. A total of 56 recommendations were formulated, with 53 achieving a high level of consensus (≥90%). These updated guidelines represent a major step forward toward harmonizing MRD assessments in AML and enhancing its clinical utility across diverse treatment settings.

In this review, we explore the role of complex interactions between genomic evolution, environmental and genetic predispositions, and immune surveillance in disease progression from precursor conditions smoldering multiple myeloma and monoclonal gammopathy of undetermined significance to multiple myeloma (MM). MM has been described to be universally preceded by precursor states, often decades before it is even diagnosed. Genetic predisposition plays an important role in the initial transformation, and is driven by both germline variants and MM-specific loci influencing risk. The reported disparities in occurrence of precursor conditions and MM among racial groups highlights the role of predisposition and the need for broader cohort studies. Early genomic events, such as translocations and hyperdiploidy, are essential in precursor initiation. However, additional factors are usually needed to transform the precursor stages into symptomatic disease, such as positive selection of subclonal populations. This process is affected by aging and environmental factors, such as exposures to Agent Orange and agrochemicals. Therefore, integrating genomic and transcriptomic data with immune profiling or other clinical features is essential for identifying patients with high risk of progressing into MM. Here, we highlight the complexity of myelomagenesis, and underline the importance of state-of-the-art approaches for improved disease prediction.

The cyclooxygenase (COX) signaling pathway is frequently dysregulated in cancer, resulting in the aberrant production of prostaglandins, a distinct class of bioactive lipids with immunoregulatory functions. One of these factors, prostaglandin E2 (PGE2), has over the years emerged as a predominant COX-derived factor in tumors, with numerous studies exploring its downstream signaling and functional impact across diverse cell types. Recent studies have substantially advanced our understanding of how PGE2 promotes cancer immune evasion through its deleterious effects on tumor-infiltrating immune cells. Here, we summarize some key principles of PGE2-mediated immune regulation in tumors, focusing on the current knowledge of PGE2 production mechanisms and recent advances in our understanding of molecular features and functional consequences of PGE2 signaling in innate and adaptive immune cells. We further discuss how strategies aimed at disrupting the local activity of prostaglandins in tumors, or interfering with the distinct molecular features characteristic of PGE2 signaling in immune cells, may provide attractive new avenues for cancer therapy.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder characterized by unchecked immune activation and hyperinflammation, resulting in end-organ tissue damage and high mortality rates in untreated patients. Since the first description of this condition in 1939, our understanding of HLH has continued to deepen, with increasing appreciation of the differences and similarities between primary (familial) HLH and secondary (acquired) HLH. Primary HLH typically presents in the early years of life on the backdrop of inherited genetic mutations affecting cytotoxic immune cell function, whereas secondary HLH more commonly presents in adults and is a heterogeneous disorder with various potential triggers ranging from infections to malignancy, autoimmune disease, immunodeficiency, and medications. However, they converge in a common pathway of widespread systemic inflammation, which clinically manifests with fevers, organomegaly, cytopenias, laboratory derangements, and rapid development of multiorgan failure. As such, early recognition and intervention is critical to prevent irreversible organ damage and death in both primary and secondary HLH. In this review, we focus our attention on adult-onset secondary HLH and explore the latest updates on the pathophysiology, precipitants, clinical presentation, diagnosis, and management of this life-threatening condition. Primary HLH is reviewed separately as a companion article in this review series.

Aside from allogeneic transplantation, the current standard-of-care approach for higher-risk myelodysplastic syndromes/neoplasms (HR-MDS) remains monotherapy with a hypomethylating agent (HMA), including azacitidine, decitabine, or oral decitabine/cedazuridine. Many attempts using HMA-based combinations have failed to improve upon HMA monotherapy. Although promising efficacy was observed in early-phase clinical trials with several agents, subsequent randomized phase 3 trials failed to confirm improvements in complete response rates or overall survival. In this review, we discuss lessons learned from the recently reported negative trials of azacitidine in combination with eprenetapopt (APR-246), magrolimab, pevonedistat, sabatolimab, tamibarotene, and venetoclax. First, we make a case for emphasizing biological classification rather than disease risk status alone to select patients for HR-MDS trials. Second, we argue that patients with TP53-inactivated MDS and chronic myelomonocytic leukemia should be treated in dedicated clinical trials. Alternatively, if TP53-inactivated MDS is included in HR-MDS trials, then randomization stratification by TP53 inactivation status should be considered. Third, we caution against ignoring signals of excessive toxicity and premature discontinuation of investigational agent observed in early-phase trials. Fourth, we show that the International Working Group (IWG) 2006 response criteria, long used in HR-MDS trials, can both overestimate and underestimate the true therapeutic benefit. Instead, we advocate for using the IWG 2023 response criteria to better capture clinically meaningful benefits in HR-MDS. Lastly, we emphasize the need for the scientific community to access patient-level data and samples from failed phase 3 trials in an efficient and expedited fashion to inform the development of subsequent trials.

Classic Hodgkin lymphoma (cHL) is highly curable with risk-adapted first-line treatment. Due to exceptional efficacy, antiprogrammed cell death protein 1 antibodies (aPD1) are increasingly incorporated into first-line treatment. However, the short- and long-term immune-related adverse event burden in this setting is insufficiently understood. Here, we review the currently available evidence on the feasibility and safety of aPD1 first-line cHL treatment. A more harmonized and complete reporting is critical to enable a detailed understanding and comprehensive assessment of aPD1-related morbidity.

The BCR::ABL1 tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML) represent a paradigm for molecularly targeted therapy. However, clinical outcomes (rate/depth of response, treatment-free remission [TFR], progression to blast crisis [BC]) and adverse events vary among patients. While additional somatic mutations have been invoked to explain varying clinical outcomes, we here propose a complementary perspective based on single-cell omics (sc-omics) approaches that have enabled unprecedented resolution of the cellular ecosystems, including their composition, interactions, and activity. In patients who were treatment-naïve and in chronic phase (CP), this has revealed differences in the growth-rate of BCR::ABL1+ clones, ratio of TKI-insensitive leukemic stem cells (LSC) to residual hematopoietic stem cells (HSC), and immune cell composition, factors that collectively contribute to variability in therapy efficacy. Together these findings suggest that cellular heterogeneity serves as a foundation of clinical outcome in CML. Patients who remain in CP exhibit an erythroid signature in LSC, while those progressing to BC manifest an inflammatory profile, additional mutations, and expansion of early progenitors. Deep responders with active natural killer, and regulatory T cells are more likely to sustain TFR. Similarly, the outcomes of donor lymphocyte infusion after allogeneic stem cell transplant are heterogeneous, and reflect differences in preexisting T-cell clonotypes, their expansion, and interaction with leukemic cells in responders vs nonresponders. Here, we summarize key insights from sc-omics in CML, and propose an actionable road map to further leverage these technologies. This includes mechanistically explaining heterogeneity, predicting therapy response and BC, tracking leukemogenic clones longitudinally, targeting TKI-insensitive LSC, and restoring hematopoiesis from residual HSCs.

The European LeukemiaNet has periodically issued guidelines for the diagnosis and management of acute myeloid leukemia (AML) in adults. These consensus recommendations, most recently updated in 2022, incorporate recent advances in genomic testing, disease detection methods, target identification, and response assessment. Although similarities exist between AML in children and adults, pediatric AML is frequently characterized by unique cytogenetic and molecular features, which require distinct genetic and immunophenotypic diagnostics, therapeutic approaches, response assessment criteria, and supportive care strategies. To address these specific needs, an international panel of pediatric hematologist-oncologists, biologists, geneticists, and laboratory medicine scientists convened to develop recommendations for the diagnosis and management of AML in children, adolescents, and young adults (hereafter termed pediatric AML) that are discussed in this special report.

The peptide hepcidin is produced by the liver and serves as the central negative regulator of iron trafficking. Recently, drugs that affect the hepcidin pathway have been evaluated as potential treatment options for both controlling the degree of erythrocytosis in patients with polycythemia vera (PV) as well as correcting anemia associated with myelofibrosis (MF). Under normal conditions, increased hepcidin levels limit iron absorption from the gastrointestinal tract and iron recycling from liver and splenic macrophages, thus decreasing plasma iron levels and restricting iron availability for erythropoiesis. In PV, however, unrestricted erythropoiesis occurs despite low systemic iron levels. Because hepcidin levels are relatively low in patients with PV, hepcidin agonists (rusfertide, divesiran, sapablursen) are undergoing clinical development to control PV-associated erythrocytosis, thereby reducing the need for therapeutic phlebotomies and myelosuppressive therapeutic options. By contrast, hepcidin levels are increased in patients with MF leading to the trapping of iron in tissue macrophages, which creates a picture that resembles anemia of chronic inflammation. A number of strategies to lower hepcidin levels (the Janus kinase 2 inhibitors pacritinib and momelotinib, anti-hemojuvelin monoclonal antibody DISC-0974C) are currently undergoing clinical development to make systemic iron available for erythropoiesis and alleviate the degree of MF-associated anemia. These new therapeutic options that modulate iron trafficking in patients with PV and MF represent the application of greater knowledge of iron trafficking to create novel therapeutic options to treat patients with hematological malignancies.

Blood platelets are crucial in hemostasis, thrombosis, and thromboinflammation. Current evidence highlights the considerable heterogeneity within individuals in platelet structure, age, and activation properties. This heterogeneity has major implications for the diverse functions of platelets in physiology and pathophysiology, extending to therapeutic targeting in hemostasis and cancer. In this review, we provide a general concept of heterogeneity or diversity of platelet populations, with emphasis on the diagnostic and advanced methodologies to assess and study differences between platelets. We describe conventional and novel approaches to address clinical and in research questions addressing platelet heterogeneity and discuss strengths and limitations of the available techniques.

Marginal zone lymphomas (MZLs) are a heterogeneous group of low-grade B-cell neoplasms classified into different entities by the current lymphoma classifications. They share some features, but differ significantly in clinical presentation, associated inflammatory conditions, anatomic sites of involvement, and molecular alterations. Etiopathogenesis is strongly linked to chronic antigenic stimulation and specific infections or autoimmune disorders for extranodal disease. Genetic hallmarks include constitutive NF-κB activation and common trisomies 3 and 18, alongside subtype-specific lesions such as translocations in extranodal MZL, recurrent KLF2/NOTCH2 mutations in both nodal and splenic MZL, and deletions involving chromosome 7q, predominantly observed in splenic MZL. Diagnosis can be challenging due to overlapping features with other lymphomas such as follicular and lymphoplasmacytic lymphomas; integrating morphology, immunophenotype, and molecular data is essential. Transformation to aggressive diffuse large B-cell lymphoma occurs in 3% to 15% of cases and is associated with the accumulation of genetic lesions, particularly in cell cycle, NF-κB, and epigenetic regulators, with subtype-specific drivers including TNFAIP3, TP53, and CDKN2A/B alterations. The tumor microenvironment plays a critical but understudied role, influenced by chronic antigen stimulation and involving complex interactions with immune cells that can promote immune suppression and influence therapeutic response. Understanding the heterogeneity of MZLs across their classification, genetic landscapes, and interaction with the microenvironment is crucial for accurate diagnosis, prognosis, and the development of effective targeted therapies.

Marginal zone lymphoma (MZL) comprises a biologically heterogenous group of indolent B-cell lymphomas that remain substantially underrepresented in clinical research. Despite recent and significant therapeutic advances in B-cell malignancies, trial design in MZL continues to face persistent challenges, including diagnostic heterogeneity, inconsistent control arms, suboptimal end points, and economic barriers. In this narrative review, we examine these key obstacles and discuss emerging strategies to overcome them, such as the standardization of diagnostic criteria, implementation of subtype-specific treatment approaches, validation of surrogate end points, and integration of novel response assessment modalities, such as metabolic imaging (positron emission tomography), minimal residual disease assessment using flow cytometry or single-cell molecular evaluation, and circulating tumor DNA measurement, but these need to be evaluated and harmonized for full appreciation. We argue that MZL should be understood as a methodologic paradigm rather than as a clinical exception. This may facilitate the refinement of trial design and ultimately accelerate therapeutic innovation across the broad spectrum of indolent lymphomas.

Platelets in peripheral blood critically drive clot formation in health and disease. Previously considered to uniformly respond to vascular injury and inflammatory cues, recent studies have highlighted that circulating platelets exhibit marked heterogeneity, with distinct populations contributing differentially to hemostasis, thrombosis, and inflammation. In this review, we highlight platelet diversity as a consequence of origin (ie, megakaryocyte diversity), circulatory age (ie, young vs aged platelets), and, specifically, as both a sequela of and a contributing factor to cardiovascular and inflammatory diseases. This diversity includes reticulated platelets (RPs), newly released from the bone marrow, RNA-rich, and highly prothrombotic, vs aged platelets, which exhibit altered receptor expression and proinflammatory rather than hemostatic features. We further describe how platelet subsets actively shape disease progression. Hyperreactive RPs drive arterial thrombosis, whereas procoagulant platelets amplify fibrin formation in venous thromboembolism. In chronic inflammation, interactions of immune-responsive platelets with leukocyte subsets facilitate their recruitment and impact on polarization, but can also promote endothelial dysfunction and immune hyperactivation, perpetuating thromboinflammatory dysregulation. Moreover, platelet phenotypes are dynamically regulated by disease states, with systemic inflammation, altered shear forces, and metabolic stress influencing platelet turnover, activation thresholds, and functional specialization. Recognizing platelet heterogeneity in disease pathogenesis could provide new opportunities for precision medicine, potentially allowing stratification of thrombotic risk and differential tailoring of antiplatelet and anti-inflammatory therapies.

The discovery of calreticulin (CALR) mutations in patients with myeloproliferative neoplasms (MPNs) has paved the way for the elucidation of a unique disease mechanism that is particularly well suited to targeting by biologics. All MPN-associated pathogenic CALR mutations are characterized by a frameshift, resulting in translation of the same neoantigen peptide. This neoantigen directly activates the thrombopoietin receptor, leading to uncontrolled neoplastic cell proliferation. Current therapeutic approaches for MPNs are focused primarily on blood count control. Furthermore, current approaches are neither disease modifying nor clonally selective. However, because the mutant CALR neoantigen peptide is functional and not expressed in normal physiology, it is an ideal drug target. Here, we review the structure and function of mutant CALR, including the subtle yet clinically and therapeutically relevant differences between the 2 most commonly occurring types of mutation. We also review the current therapeutic landscape for CALR-mutated MPNs, highlighting the areas in which current approaches are inadequate. Finally, we review ongoing clinical and preclinical experimental approaches for targeting mutant CALR in MPNs in a clonally selective manner using monoclonal antibodies, bispecific antibodies, cancer vaccination, chimeric antigen receptor T cells, and antibody-drug conjugates. Taken together, we expect that ongoing developments in mutant CALR-targeted therapeutics will lead to promising novel strategies for long-term disease control.