Remarkable progress in the understanding of disease pathogenesis and treatment across hematologic malignancies has been achieved in the past 2 decades. Nevertheless, the reliable elimination of disease remains elusive for many cancers. Chronic lymphocytic leukemia (CLL) exemplifies the needs that must be addressed to close the gap between discovery science and the remaining clinical challenges. In CLL, targeted therapies have substantially prolonged survival and enabled long-term disease control for many patients. However, curative outcomes remain exceptional, particularly in high-risk groups such as those with TP53 disruption, dual resistance to Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors, or transformation to aggressive lymphoma. Recent insights into the interconnection between cancer and immunity have positioned CLL as a model example of cancer-associated immunodeficiency, a realization brought into sharp focus by the severe acute respiratory syndrome coronavirus 2 pandemic during which patients with CLL were at extremely high-risk for infection and poor outcomes. Therefore, complications related to infections, autoimmunity, and secondary cancers continue to contribute substantially to morbidity and mortality, underscoring the need for research on immune dysfunction in CLL. Furthermore, pronounced heterogeneity in disease progression and therapeutic resistance highlight the need for mechanistic studies to clarify these distinct biological patterns. Advances in these areas not only hold the promise of curative therapy for broader patient subgroups in CLL but will also inform innovation in research on other cancers, particularly in establishing a molecular definition of disease and defining those interactions with the underlying and resultant immune deficiencies.

Hairy cell leukemia (HCL) and HCL variant (HCLv) are distinct, rare, and chronic splenic B-cell lymphomas/leukemias that partially overlap in clinicopathologic presentation but differ in genetic basis, prognosis, and management. HCL is caused by the BRAF-V600E kinase-activating mutation in >95% of the patients, usually has excellent responses to chemotherapy with purine analogues, and is also amenable to BRAF inhibitor-based targeted treatments. In contrast, HCLv lacks BRAFV600E mutation, requires combined therapy with purine analogues in addition to rituximab, and generally shows less durable responses. Here, an international team of hematologists, experts on these rare diseases, was convened by the Hairy Cell Leukemia Foundation to update the previous guidelines (published in 2017) by providing a summary of current methods to diagnose and manage patients with HCL and HCLv as well as a prospective on newer targeted therapies to further improve outcomes.

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia caused by monoclonal immunoglobulin M autoantibodies that bind to red blood cells and trigger hemolysis through activation of the classical complement pathway. Cold agglutinins are produced by a clonal population of lymphocytes, recognized by the World Health Organization as a low-grade lymphoproliferative disorder. Traditional therapy relied on B-cell-targeted immunosuppression with rituximab, which mainly yielded partial responses in approximately half of the patients. The combination of rituximab with fludarabine or bendamustine significantly increased and prolonged response rates, although with a substantial infectious risk. Sutimlimab, the first C1s complement inhibitor, has shown efficacy in rapidly and sustainably increasing hemoglobin levels, reducing hemolysis, and significantly improving quality of life. However, the drug does not act on the B-cell clone and does not decrease cold agglutinins. Therefore, several unmet needs remain, including identifying patients who can discontinue sutimlimab while maintaining remission, developing combination strategies effective against cold-induced symptoms, and improving infection prevention and control of hemolytic flares. This perspective article briefly recapitulates the pathophysiology of CAD, outlines the evolution of its treatment landscape, and focuses on the role of sutimlimab, including its clinical positioning, therapeutic benefits, and management considerations, offering insights into optimizing care for patients with this challenging condition.

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.

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 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.

Until recently, the JAK1/2 inhibitor ruxolitinib (Jakafi) was the only therapy for steroid-refractory acute graft-versus-host disease approved by the US Food and Drug Administration (FDA) for use in patients aged >12 years. The FDA has now approved a potent mesenchymal stromal cell product, remestemcel-L-rknd (Ryoncil), for children aged ≤18 years, showing 70% response rates and ∼70% 6-month survival. In this spotlight, we highlight this important advance in the field.

TP53 mutations are found in 10% to 15% of myeloid neoplasms and are one of its most important prognostic factors. Emerging data show that TP53 mutational allele status is a key determinant of clinical outcomes, with multihit TP53 mutant myeloid neoplasms having a very poor prognosis. Significant differences exist among the methods used in clinical and research settings to assess TP53 mutational status, leading to variability in reported patient characteristics, response to therapy, and survival. Indeed, differences in the criteria used to define TP53 mutational states among professional societies and in landmark research studies have led to confusion, suboptimal clinical testing, and variability in therapy recommendations. We review the methods used to assess for TP53 mutational allele status and provide recommendations, based on clinically available testing, for the accurate evaluation of TP53 gene mutations in myeloid neoplasms. Hotspot mutations represent ∼35% of all TP53 missense mutations in myeloid neoplasms. There is evidence that these hotspot mutations may have dominant-negative or gain-of-function properties. Here, we review this evidence and discuss the potential impact of TP53 mutation identity on patient outcomes and clinical management.

In 2013, we published a Perspective titled "The myth of the second remission of acute leukemia in the adult," which underscored the dismal outcomes of relapsed acute leukemia in adults. We emphasized that only a few patients achieved second complete remission (CR2) after relapse and were subsequently eligible to receive a potentially curative allogeneic hematopoietic stem cell transplantation (HSCT). Hence, we urged the leukemia community not to delay HSCT in first complete remission if indicated to avoid dire outcomes. Historically, poor outcomes resulted from suboptimal frontline therapy, inadequate risk stratification, and lack of effective agents to achieve CR2. In the past decade, remarkable progress has been made in the treatment paradigm of acute leukemia, most evidently in B-cell acute lymphoblastic leukemia. Key advancements include refinement of frontline treatment, incorporation of early immunotherapy, improved disease risk stratification based on molecular profiling and assessment of measurable residual disease, and discovery of highly effective salvage immunotherapies. These innovations have led to a high rate of cure by frontline therapy, precise selection for HSCT in first complete remission for high-risk patients, and the reality of HSCT for patients in CR2. Here, we re-evaluate the myth of CR2 given the progress in the field.

Heavy menstrual bleeding (HMB) is a widespread occurrence among women of reproductive age and inflicts a substantial impact on their well-being and on health care expenses. To better characterize the genetic architecture of HMB, we conducted a meta-analysis of the summary statistics of genome-wide association studies (GWAS) from 5 biobanks that included up to 84 633 HMB cases and 598 195 controls from several ancestries. Of the 21 signals significantly associated with HMB in a discovery GWAS meta-analysis that combined 4 biobanks, 20 had a concordant direction of effect in the remaining cohort, including 10 that were significantly replicated. By combining the discovery and replication data sets, 15 additional signals were identified in subsequent meta-analyses. These genetic analyses identified 36 signals (33 novel) that were significantly associated with HMB, and gene prioritization techniques (eg, transcriptome-wide association studies, polygenic priority score) subsequently revealed likely causal genes. Notable discoveries included the strong protective effect of the F5-Leiden variant (rs6025-T; odds ratio, 0.75; P = 6.8 × 10-33); variants at the FSHB and LHB/CGB loci, both involved in hormone production regulation; and several signals near genes involved in the Wnt/β-catenin signaling pathway. We also observed strong and significant genetic correlations with disorders of the female genital tract, including uterine fibroids, endometriosis, or ovarian cysts. Overall, we identified 33 novel genetic loci associated with HMB, thereby significantly improving our understanding of the genetic etiology of this condition, which may provide new targets for the development of therapeutic strategies.

Thrombotic thrombocytopenic purpura (TTP) is a rare, potentially fatal thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif 13) deficiency. Prompt treatment improves survival; however, reference standard enzyme-linked immunosorbent assay and FRETS-VWF73 ADAMTS13 activity assays have long turnaround times (TATs) that necessitate empiric treatment of many patients who ultimately are found not to have TTP. Rapid assays with analytical TATs <1 hour have recently become available. We conducted a systematic review and meta-analysis of the performance characteristics of rapid assays relative to reference standard assays for ADAMTS13 activity for patients with suspected or confirmed TTP. Nineteen studies representing 3 rapid ADAMTS13 assays and 4207 patient samples were included. The HemosIL AcuStar chemiluminescence immunoassay (CLIA) demonstrated high sensitivity (0.98; 95% confidence interval [CI], 0.94-1.00), specificity (0.99; 95% CI, 0.97-1.00), and positive (PPV) (0.96; 95% CI, 0.90-0.98) and negative predictive values (NPV) (0.99; 95% CI, 0.99-1.00). The Technofluor fluorescence resonance energy transfer (FRET) and Technoscreen assays had sensitivity of 0.93 (95% CI, 0.86-0.96) and 0.98 (95% CI, 0.42-1.00), specificity of 0.98 (95% CI, 0.95-0.99) and 0.87 (95% CI, 0.76-0.94), PPV of 0.97 (95% CI, 0.85-1.00) and 0.71 (95% CI, 0.59-0.80), and NPV of 0.96 (95% CI, 0.93-0.98) and 0.99 (95% CI, 0.72-1.00), respectively. The proportion of discrepant results (relative to reference standard assays) was 0.04 (95% CI, 0.03-0.05) for HemosIL AcuStar, 0.04 (95% CI, 0.02-0.06) for Technofluor FRET, and 0.11 (95% CI, 0.07-0.16) for the Technoscreen assay. With rapid TAT and high sensitivity, the HemosIL AcuStar CLIA seems able to reliably avert empiric plasma exchange, corticosteroids, and caplacizumab in patients without TTP.

Richter transformation (RT) is defined as an aggressive lymphoma emerging in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Despite novel therapeutics developed in CLL, RT is associated with poor outcomes. In light of recent progress regarding the diagnostic procedures and therapeutic concepts of RT, an international group of experts, under the coordination of the European Research Initiative on CLL, has developed consensus recommendations for clinical procedures and future research on this disease. Patients with RT typically present with a rapid clinical decline, worsening B-symptoms, elevated lactate dehydrogenase, and/or rapidly enlarging lymphadenopathy. Workup should include a positron emission tomography-computed tomography scan for patients with suspected RT. An excisional biopsy should be taken from an accessible lesion, preferably with the highest fluorodeoxyglucose avidity, and analyzed for the presence of aggressive lymphoma. The molecular relationship to the original CLL clone(s) should be defined. Because no effective standard treatment for RT exists, patients should be treated in a clinical trial. Response of both RT and CLL should be assessed at an early time point, and survival end points should be prioritized in trial design. We hope that these recommendations can help to harmonize clinical and translational research and improve outcomes for patients with RT.

Breakthrough hemolysis (BTH) is the hemolytic exacerbation occurring in a patient with paroxysmal nocturnal hemoglobinuria (PNH) on treatment with anticomplement therapies. In this review article, we analyzed the definition, frequency, and severity of BTH events across phase 3 clinical trials with terminal (anti-C5 ravulizumab and crovalimab) and complement inhibitors upstream C5 (anti-C3 pegcetacoplan, alternative-pathway inhibitors iptacopan, and danicopan), as well as from real-world reports. Furthermore, we reviewed the impact of the various compounds on quality of life and patient-reported outcomes. In particular, BTH may occur with all complement inhibitors, with a frequency of 10% to 15% over 6 months with eculizumab, crovalimab, and pegcetacoplan, and <5% with ravulizumab, iptacopan, and danicopan plus anti-C5. By prolonging the follow-up, the frequency of BTH appeared increased in patients treated with pegcetacoplan (nearly 24% at 1 year) as compared with both anti-C5, iptacopan, and double inhibition with danicopan plus anti-C5. BTH risk appears associated with patients' features, particularly suboptimal response/failure of previous complement inhibitor. Transfusions were required in approximately half of cases and modifications of anticomplement therapy included anticipation of the next anti-C5 dose and addition of eculizumab in patients on proximal inhibitors. Breakthrough thromboses were rare, although anticoagulant prophylaxis should be considered during severe episodes. Complement amplifying conditions were observed in approximately half of cases and were more frequently infections. Treatment adherence, optimization of the administration schedule, anticoagulant prophylaxis, as well as education of patients and physicians remain important factors to prevent BTH and its complications.

Hereditary stomatocytosis represents a heterogeneous group of inherited erythrocyte membrane defects characterized by hemolytic anemia of variable degree, with alterations in cellular salt and water, ranging from dehydration to overhydration, and the presence of stomatocytes on peripheral blood smear. This condition encompasses various subtypes, each with distinct clinical and genetic features. The pathophysiology underlying these conditions involves altered red blood cell membrane properties, leading to impaired deformability and alterations in cation permeability and volume, causing increased susceptibility to hemolysis. Advancements in genetic testing have enabled the identification of some causative genes in the last years, such as PIEZO1, KCNN4, and ABCB6. These genetic discoveries have facilitated a deeper understanding of the molecular mechanisms underlying the pathogenesis and have paved the way for improved diagnostic accuracy and genetic counseling. This review provides an overview of the clinical presentation, pathophysiology, molecular genetics, diagnosis, and management strategies of hereditary stomatocytosis, highlighting recent advancements in the field of dehydrated hereditary stomatocytosis (DHS), or hereditary xerocytosis, and hepatic iron overload. This latter is directly associated with the physiological role of PIEZO1, the causative gene of DHS, at hepatic and macrophagic levels. Particularly, gain-of-function mutations in PIEZO1 account for a pleiotropic syndrome characterized by different phenotypes depending on the expression of PIEZO1 in multiple cells and tissues.

Targeted therapy with covalent Bruton tyrosine kinase inhibitors (cBTKis) and/or the B-cell lymphoma 2 inhibitor (BCL-2i) venetoclax is now well established in the first-line management of chronic lymphocytic leukemia (CLL). However, patients with "double-refractory" disease due to the acquired resistance to both drug classes represent an increasing clinical challenge for whom few well-tolerated and effective treatment options currently exist. The highly selective, noncovalent BTKi pirtobrutinib and CD19-directed chimeric antigen receptor T-cell therapy lisocabtagene maraleucel have both recently gained US Food and Drug Administation approval for use in patients with CLL, which has progressed following ≥2 prior lines, including a cBTKi and a BCL-2i. Additionally, novel BTK-directed therapies and T-cell-engaging bispecific antibodies have achieved promising responses in pretreated CLL in early-phase clinical trials. Here, we review the mechanisms responsible for resistance to cBTKi and venetoclax in CLL, appraise recent evidence supporting the use of each of the novel and emerging agent classes, and then suggest innovative treatment strategies incorporating these in patients with double-refractory disease, remaining cognizant of the variability of access to novel therapies and clinical trials.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder, characterized by thrombocytopenia, eczema, recurrent infections, autoimmunity, and malignancy. Here, we discuss current conservative and definitive approaches to treating WAS, based on recently published evidence. Disease severity in WAS is highly variable. Recent studies confirm that the probability of disease progression depends on the type of genetic variant, supporting early diagnosis and tailored treatment strategies. Milder cases, historically termed X-linked thrombocytopenia (XLT), received supportive care, whereas severe cases were referred for standard allogeneic hematopoietic cell transplantation (HCT) or gene therapy (GT) in clinical trials. Advances in HCT and GT, together with recent knowledge that even patients with XLT are at risk for severe immune complications, suggest that most young patients with WAS should be offered a potentially curative approach at diagnosis. Older patients with a small subset of milder variants may be treated conservatively unless they develop life-threatening autoimmune or malignant complications; regular monitoring and proactive management are critical to preventing irreversible complications. We recommend discontinuing the term XLT as it implies a mild and uncomplicated disease, which is not the norm, and instead tailor treatment for all patients with WAS to their individual genetic profile, disease severity, and clinical course.

Excessively restrictive inclusion and exclusion criteria in clinical trials are one of many barriers to clinical trial enrollment for patients with myelodysplastic syndromes/neoplasms (MDSs). Many organizations are developing efforts to increase clinical trial eligibility; yet, several recent publications focused on patients with MDS suggest that many patients with this disease may be excluded from clinical trials unnecessarily. Clinical trial eligibility should reflect the phase of the study and risks of the agent being studied. Phase 3 trials should be less restrictive than early-phase trials to represent the real-world population as closely as possible. We hypothesize that many clinical trials, particularly phase 3 trials, have unnecessarily restrictive eligibility criteria. This study aims to evaluate the most common eligibility criteria according to phase of trial and to determine whether criteria correspond with drug safety signals. We identified MDS clinical trials registered on ClinicalTrials.gov from 1 January 2000 to 1 September 2023 and analyzed the eligibility criteria of 191 therapeutic MDS trials. We found that categorical inclusion and exclusion criteria are remarkably similar in representation across trial phases. Additionally, only 13% of trials are concordant with drug safety signals, suggesting that the eligibility criteria are often arbitrary. On behalf of the icMDS (International Consortium for Myelodysplastic Syndromes), an association of international MDS experts, we provide a position statement on restrictive eligibility criteria for MDS clinical trials that should be avoided with the aim of removing barriers to clinical trial enrollment.

Venous thromboembolism, which includes deep vein thrombosis (DVT) and pulmonary embolism, is a common cardiovascular disorder associated with significant morbidity and mortality. Current treatment options primarily involve anticoagulants, which reduce the risk of fatal events and DVT recurrence but increase the risk of bleeding, particularly in people requiring prolonged thromboprophylaxis. Growing evidence characterizes DVT as a complex inflammation-driven process rather than a merely coagulation-dependent thrombosis, with endothelial cells, neutrophils, and platelets playing major roles in its initiation. Recent studies demonstrate that these cell types undergo profound metabolic reprogramming in response to stasis, hypoxia, and inflammatory stimuli, including shifts in glycolysis, the pentose phosphate pathway, and redox balance. This review summarizes current insights into these metabolic adaptations, examines evidence from preclinical DVT models showing that targeting metabolic pathways can reduce venous thrombus formation without impairing hemostasis, and highlights potential metabolic targets for intervention. By modulating metabolic pathways that underlie the prothrombotic and proinflammatory phenotypes, it may be possible to prevent DVT initiation or limit its progression while reducing the reliance on anticoagulants and the risk of associated bleeding complications. This metabolism-centered perspective opens new avenues for the development of safer, more effective treatments for DVT.

Hemorrhage causes millions of deaths and hundreds of billions of dollars in medical costs every year, and a large percentage of trauma bleeding-associated deaths occur in the prehospital setting. Bleeding is typically treated with transfused blood products, but this is difficult in the prehospital setting due to limitations in transportation and storage, especially in rural and remote military settings. Advancements in cold-stored platelets and lyophilized blood products have the potential to address some of these limitations. However, devising novel products that continue to improve shelf life, portability, scalability, cost, and safety for patients experiencing bleeding in prehospital settings could greatly improve treatment options and patient outcomes. This review primarily focuses on rational design of material-based approaches to develop novel hemostatic agents that strive to meet limitations of current blood products, especially for use in the prehospital setting. Key topics of consideration include how material design can lead to identification of effective therapies that stop bleeding as well as strategies to iterate on existing designs to enhance healing after cessation of bleeding. Improving performance and functionality of existing and emerging materials could be achieved through the incorporation of transglutaminases, growth factors, cellular components, or inorganic molecules. Finally, consideration of patient-specific factors that influence bleeding, such as patient sex and age, through evaluation of therapies in specific populations and/or design of materials targeted for specific patient populations, is a key area for development of next-generation hemostatic materials.

"Nonclassical" myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field.