Patients with thrombocytopenia requiring ongoing platelet transfusion support may develop inadequate platelet count increments, referred to as platelet refractoriness (PR), which further complicates their care. The underlying etiologies of PR can be broadly divided into immune and nonimmune causes. A high index of suspicion is required to initiate testing for alloimmunization, and the leading culprit in immune PR is the development of class I HLA antibodies. The approach to diagnosis of immune PR has changed over recent years with new technologies, but questions regarding the clinical significance and interpretation of these methods have not been conclusively answered. The provision of HLA-matched platelets requires close and timely coordination between transfusion services and clinical teams; however, the true impact of their provision on clinical outcomes is not clear. This paper reviews diagnostic and management challenges, appraises the existing data available to support treatment options, and identifies research gaps.

Novel CD3×CD20 bispecific antibody (BsAb) immunotherapies have entered the armamentarium for follicular lymphoma and diffuse large B-cell lymphoma based on accelerated approvals. The primary challenge in utilizing BsAbs lies in patient selection due to variable responses, unique toxicity, and health economics. To date, no validated biomarkers of therapy response exist, however data demonstrating potential clinical, imaging, and biological markers relating to BsAbs are growing. This review examines current prognostic and potentially predictive biomarkers and explores future directions for nuanced patient selection.

The UK Infected Blood Inquiry report was published in May 2024 after 6 years of taking oral and written evidence from patients, clinicians, blood services, government officials, and politicians about the transmission of infection by blood transfusion to thousands of patients in the 1970s through to the 1990s. The same problems with transfusion-transmitted infection occurred in many other countries in the same period, but their reviews, inquiries, and decisions about compensation occurred many years earlier than in the United Kingdom. The publication of the report has been welcomed but begs 2 important questions. Why was the inquiry so delayed in the United Kingdom? And why did it take so long to report? Furthermore, the report itself deserves scrutiny. What were its findings and lessons learned? How will the findings be implemented, and what are the implications, if any, for other countries?

The last decade has seen the introduction of 2 new licensed therapies for thrombotic thrombocytopenic purpura (TTP), caplacizumab and recombinant ADAMTS13 (rADAMTS13), for immune and congenital TTP (cTTP), respectively. They improve acute TTP outcomes, and reduce the need for plasma therapy, time to clinical response, and treatment burden. Future pathways need to replace plasma exchange in acute TTP and optimize/personalize rADAMTS13 in cTTP. Future emphasis should focus on additional monoclonals/treatments to tackle ADAMTS13 antibodies.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL) invariably develops from a background of chronic inflammatory disorder caused by a diverse chronic microbial infection and/or autoimmunity, depending on the site. These chronic inflammatory/autoimmunity disorders trigger innate and acquired immune responses, generating a unique microenvironment at each site that drives clonal evolution of B cells, their expansion, and eventual malignant transformation. At a molecular level, this involves temporal and spatial acquisition of cooperative oncogenic events by dysregulated immune responses and somatic genetic changes. Although these events are not yet fully characterized, EMZL at several sites shows distinct genetic profiles and molecular insights, bridging the pathologic process to lymphomagenesis. For example, gastric EMZL, particularly those lacking a BCL10 or MALT1 translocation, critically depends on T-helper cell signals produced by immune responses to Helicobacter pylori infection. Likewise, thyroid EMZL may also involve exaggerated T-cell help because of highly frequent inactivating mutations in TET2, CD274 (programmed cell death 1 ligand 1), and TNFRSF14, which impede the coinhibitory interactions between the neoplastic B- and T-helper cells, thus releasing T-cell help. Ocular adnexal EMZL shows frequent TNFAIP3 (A20) mutation/deletion that significantly associates with expression of autoreactive IGHV4-34 B-cell receptor, emphasizing its potential cooperation in NF-κB pathway activation. Finally, the genesis of salivary gland EMZL may be closely associated with GPR34 activation that is caused by mutation/t(X;14)(p11;q32) and/or paracrine stimulation mediated by ligand generated by lymphoepithelial lesions. This review will focus on these novel molecular insights and how these advances may provide a paradigm for future investigations.

Globally, an estimated 300 million individuals have sickle cell trait (SCT), the carrier state for sickle cell disease (SCD). Although SCD is associated with increased morbidity and shortened life span, SCT has a life span comparable with that of the general population. However, "sickle cell crisis" has been used as a cause of death for decedents with SCT in reports of exertion-related death in athletes, military personnel, and individuals in police custody. To appraise this practice, the American Society of Hematology convened an expert panel of hematologists and forensic pathologists to conduct a systematic review of the literature relating to the occurrence of sickle cell pain crises and exertion-related mortality in people with SCT. Multiple bibliographic databases were searched with controlled vocabulary and keywords related to "sickle cell trait," "vaso-occlusive pain," and "death," yielding 18 of 1474 citations. Independent pairs of reviewers selected studies and extracted data. We found no studies comparing uncomplicated acute pain crises in individuals with SCT and SCD. Additionally, no study was identified to support the occurrence of acute vaso-occlusive pain crises in individuals with SCT. Furthermore, this systematic review did not identify any evidence to support an association between SCT and sudden unexplained death in the absence of exertion-related rhabdomyolysis. We conclude that there are no data to support the diagnosis of acute vaso-occlusive sickle cell crisis as a cause of death in SCT, nor does the available evidence support the use of SCT as a cause of exertion-related death without rhabdomyolysis.

Desmopressin (1-desamino-8-d-arginine vasopressin [DDAVP]) can be used to prevent or stop bleeding. However, large interindividual variability is observed in DDAVP response and determinants are largely unknown. In this systematic review and meta-analysis, we aimed to identify the response to DDAVP and the factors that determine DDAVP response in patients. We included studies with patients with any bleeding disorder receiving DDAVP. First and second screening round and risk of bias assessment were performed by independent reviewers. The main outcome was proportion of patients with complete (factor level >50 U/dL) or partial (30-50 U/dL) response to DDAVP. Determinants of response including disease type, age, sex, von Willebrand factor (VWF) and factor VIII (FVIII) mutations, and baseline factor levels were investigated. In total, 591 articles were found and 103 were included. Of these, 71 articles (1772 patients) were suitable for the study's definition of response. Meta-analysis showed a pooled response proportion of 0.71 (0.64; 0.78) and a significant difference in response between disease subtypes. For hemophilia A, baseline FVIII activity (FVIII:C) was a borderline significant determinant of response. In patients with von Willebrand disease (VWD) type 1, VWF antigen (VWF:Ag), VWF activity, and FVIII:C were significant determinants. A large variation in response was observed for specific mutations in VWF and FVIII. Response to DDAVP varied between disease subtypes and was largely determined by the baseline levels of FVIII:C for hemophilia A and VWF:Ag for VWD. Our findings highlight the significant differences in response and emphasize the need for a standardized response definition and further research into response mechanisms.

Myelodysplastic syndromes/neoplasms (MDS) are a widely heterogenous group of myeloid malignancies characterized by morphological dysplasia, a defective hematopoiesis, and recurrent genetic abnormalities. The original International Prognostic Scoring System (IPSS) and revised IPSS have been used to risk-stratify patients with MDS to guide treatment strategies. In higher-risk MDS, the therapeutic approach is geared toward delaying leukemic transformation and prolonging survival. For more than a decade, the hypomethylating agents azacitidine and decitabine have been the standard of care and, when feasible, an allogeneic hematopoietic stem cell transplantation should be considered. However, the IPSS scoring systems solely rely on clinical, morphological, and cytogenetic features and do not account for somatic mutations present in >80% of cases. These genetic abnormalities have been shown to play a crucial role in prognostication, prompting the development of molecular IPSS, and the integration of genomic features into MDS classification systems in recent years. In this review, we delineate our approach to higher-risk MDS in the context of updated classifications and the latest prognostication tools. We use illustrative clinical cases to support our discussion and share insights from recent clinical trials, highlighting lessons learned.

Bruton tyrosine kinase inhibitors (BTKis) are an established standard of care in chronic lymphocytic leukemia. The covalent BTKis ibrutinib, acalabrutinib, and zanubrutinib bind to BTK C481 and are all susceptible to the C481S mutation. Noncovalent BTKi, including pirtobrutinib, overcome C481S resistance but are associated with multiple variant (non-C481) BTK mutations, including those associated with resistance to acalabrutinib and zanubrutinib (T474 codon and L528W mutations). We review the current knowledge on variant BTK mutations, discuss their clinical implications, and consider their impact on clinical trials.

Anemia is a common consequence of myelofibrosis. The treatment of myelofibrosis-associated anemia is complicated by a multifactorial pathobiology and a lack of therapies that result in normalization of the bone marrow and complete restoration of its function. Established agents that are used to treat anemia in other bone marrow failure states, such as myelodysplastic syndromes and aplastic anemia, are used for the treatment of myelofibrosis-associated anemia. However, there has been rapid development of new anemia-directed therapies, some of which have garnered regulatory approval. In addition to adopting therapies from other disease states, better understating of the root causes of myelofibrosis-associated anemia has positioned the field to be on the cutting edge of new anemia treatments, spearheading the advancement of agents that work on the hepcidin pathway to improve red cell production.

Despite novel prophylactic regimens, chronic graft-versus-host disease (cGVHD) remains a challenging complication after allogeneic hematopoietic cell transplantation. cGVHD can affect multiple organs and reduces quality of life, and treatment can cause serious adverse effects. In the past 10 years, the drugs ibrutinib, ruxolitinib, belumosudil, and axatilimab were approved by the US Food and Drug Administration (FDA) for cGVHD. Here, we discuss which signaling pathways and cell types are targeted, the clinical studies that were the basis for FDA approval, and future directions for clinical research.

The term "unexplained cytopenia" is used to describe a condition characterized by peripheral blood cytopenia that cannot be attributed to identifiable causes using conventional tests or to any concomitant diseases. Unexplained cytopenia requires clinical attention and further investigation to identify individuals at risk of developing a hematologic neoplasm. The available evidence suggests that somatic mutation analysis may effectively complement the diagnostic workup and clinical management of unexplained cytopenia. Indeed, the presence or absence of somatic mutation(s) in myeloid genes shows high positive and negative predictive values for myeloid neoplasms (MNs). Mutation analysis is also crucial for identifying patients with clonal cytopenia of undetermined significance (CCUS), a condition at increased risk of developing a MN. Recently, clinical/molecular prognostic models have been developed, providing valuable tools for the personalization of clinical and molecular surveillance. Most patients with CCUS show mild cytopenia and do not require therapeutic intervention. Currently, there is no treatment approved for CCUS, and transfusion therapy is the sole therapeutic option for patients with severe symptomatic cytopenia. However, this field has been emerging as a domain of active clinical investigation. This article presents 4 case studies of patients with unexplained cytopenia, which hematologists may encounter in their clinical practice.

Significant progress in determining the molecular origins and resistance mechanisms of mantle cell lymphoma (MCL) has improved our understanding of the disease's clinical diversity. These factors greatly impact the prognosis of patients with MCL. Given the dynamic alterations in MCL clones and disease evolution, it is crucial to recognize high-risk prognostic factors at diagnosis and relapse. Clinical factors include a high MCL International Prognostic Index score with a high Ki-67 proliferation index, early disease progression within 24 months of first-line treatment, >3 previous lines of therapy at relapse, and an aggressive (blastoid or pleomorphic) histology. Molecular aberrations include dysregulated cyclin D1, an aberrant SOX11-CD70 axis, upregulated Musashi-2, MYC rearrangement, metabolic reprogramming, and epigenetic changes. Other factors that contribute to high-risk MCL include an immune-depleted microenvironment and clone adaptability with complex chromosomal anomalies and somatic mutations in TP53, NSD2, CCND1, CDKN2A, BIRC3, SP140, KMT2D, NFkBIE, SMARCA4, and NOTCH2. Ultra-high-risk MCL is indicated by the coexistence of multiple high-risk prognostic factors in the relapse setting and can portend very short progression-free survival. As MCL treatments advance toward cellular therapies, resistance to anti-CD19 chimeric antigen receptor T-cell therapy is also observed. These findings necessitate revisiting the prognostic impact of high-risk factors, current management strategies, new bi- and trispecific T-cell engagers, combination therapies, novel therapeutic targets, and next-generation clinical trials for patients with high-risk MCL. This article provides a comprehensive update on recognizing and managing high-risk MCL and encompass current practices and future directions.

Purpura fulminans (PF) is a rare but devastating complication of sepsis characterized by a highly thrombotic subtype of disseminated intravascular coagulation (DIC). A medical emergency, PF often requires the involvement of consultant hematologists to assist with diagnosis and management of patients who are in a highly dynamic and deteriorating clinical situation. Patients who survive past the first 24 to 72 hours often die from complications of unchecked thrombosis rather than shock, and survivors are usually left with severe scarring and tissue loss. Despite these challenging features, PF is a pathophysiologically distinct, homogeneous, and highly predictable form of sepsis-associated DIC for which poor outcomes are not a foregone conclusion. The fundamental pathologic lesion in PF is a failure of the anticoagulant protein C pathway, which leads to uncontrolled microvascular clotting and inadequate protein C-mediated cytoprotective effects, which are vital for survival in sepsis. Herein, we review the clinical features and diagnosis of PF. Drawing from existing clinical literature and recent advances in our understanding of the pathophysiology of PF, we describe rationally designed treatment approaches for this disorder, including repletion of natural circulating anticoagulants, use of therapeutic anticoagulation, and ways to optimize transfusion support, and we outline specific interventions that we would recommend avoiding.

Alloimmunization during pregnancy occurs when a mother produces antibodies against fetal antigens, leading to complications like hemolytic disease of the fetus and newborn (HDFN) and fetal and neonatal alloimmune thrombocytopenia (FNAIT). HDFN involves destruction of fetal red blood cells, potentially causing severe anemia, hydrops fetalis, and fetal death. FNAIT affects fetal platelets and possibly endothelial cells, resulting in risk of intracranial hemorrhage and brain damage. Traditional invasive methods for fetal antigen genotyping, like amniocentesis, carried miscarriage risks. The discovery of cell-free fetal DNA (cff-DNA) in maternal plasma enabled safe, noninvasive prenatal testing (NIPT). Initially used for Rhesus antigen D blood group typing, NIPT now covers various blood group antigens. Advances in technology have further enhanced the accuracy of NIPT. Despite challenges such as low cff-DNA fractions and complex genetic variations, NIPT has become essential in managing alloimmunized pregnancies. In NIPT it is important to prevent both false-positive results and false-negative results. Particularly in the coming decades, more possibilities for personalized antenatal treatment for HDFN and FNAIT cases will become apparent and accurate NIPT blood group antigen typing results are crucial for guiding clinical decisions. In this paper we describe this journey and provide practical tools for the clinic.

B-cell acute lymphoblastic leukemia (B-ALL) is a rare malignancy in adults, with outcomes remaining poor, especially compared with children. Over the past 2 decades, extensive whole-genome studies have identified numerous genetic alterations driving leukemia, leading to the recognition of >20 distinct subtypes that are closely associated with treatment response and prognosis. In pediatric B-ALL, large correlation studies have made genetic classification a central component of risk-adapted treatment strategies. Notably, genetic subtypes are unevenly distributed according to age, and the spectrum of genetic alterations and their prognostic relevance in adult B-ALL have been less extensively studied, with treatment primarily based on the presence or absence of BCR::ABL1 fusion. This review provides an overview of genetic subtypes in adult B-ALL, including recent biological and clinical insights in well-established subtypes as well as data on newly recognized subtypes. Their relevance for risk classification, disease monitoring, and therapeutic management, including in the context of B-cell-directed therapies, is discussed. This review advocates for continuing efforts to further improve our understanding of the biology of adult B-ALL to establish the foundation of future precision medicine in B-ALL.

Starting with imatinib, tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a lethal blood cancer into a chronic condition. As patients with access to advanced CML care have an almost normal life expectancy, there is a perception that CML is a problem of the past, and one should direct research resources elsewhere. However, a closer look at the current CML landscape reveals a more nuanced picture. Most patients still require life-long TKI therapy to avoid recurrence of active CML. Chronic TKI toxicity and the high costs of the well-tolerated agents remain challenging. Progression to blast phase still occurs, particularly in socioeconomically disadvantaged parts of the world, where high-risk CML at diagnosis is common. Here, we review the prospects of further improving TKIs to achieve optimal suppression of BCR::ABL1 kinase activity, the potential of combining different classes of TKIs, and the current state of BCR::ABL1 degraders. We cover combination therapy approaches to address TKI resistance in the setting of residual leukemia and in advanced CML. Despite the unprecedented success of TKIs in CML, more work is needed to truly finish the job, and we hope to stimulate innovative research aiming to achieve this goal.

Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the principal curative approaches in the treatment of acute myeloid leukemia (AML); however, relapse after transplantation remains a catastrophic event with poor prognosis. The incidence of relapse has remained unchanged over the last 3 decades despite an evolving understanding of the immunobiology of the graft-versus-leukemia effect and the immune escape mechanisms that lead to post-HSCT relapse. The approach to posttransplant relapse is highly individualized and is dictated both by disease biology and genomics as well as the patient's clinical status at the time of relapse and the interval between relapse and transplantation. With the help of 3 illustrative cases, we discuss our approach to early, late, and incipient relapse. Current therapeutic strategies incorporate immunosuppression taper when feasible, a variety of targeted and nontargeted chemotherapeutic agents, and consolidative cellular therapies including donor lymphocyte infusions or a second allogeneic transplant. We then summarize evolving frontiers in the treatment and prognostication of relapse, including the critical role of measurable residual disease. Finally, we emphasize enrollment on clinical trials and thoughtful discussions regarding goals of care and supporting frail patients as universal principles that should be incorporated in approaches to treatment of AML relapse after transplantation.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the (oligo)clonal expansion of myeloid progenitor cells. Despite advances in treatment, AML remains challenging to cure, particularly in patients with specific genetic abnormalities. Menin inhibitors have emerged as a promising therapeutic approach, targeting key genetic drivers of AML, such as KMT2A (lysine methyl transferase 2A) rearrangements and NPM1 mutations. Here, we review the clinical value of menin inhibitors, highlighting their mechanism of action, efficacy, safety, and potential to transform AML treatment.

Quantitative fibrinogen disorders, including afibrinogenemia and hypofibrinogenemia, are defined by the complete absence or reduction of fibrinogen, respectively. The diagnosis is based on the measurement of fibrinogen activity and antigen levels, which define the severity of this monogenic disorder. Afibrinogenemia is the result of homozygosity or combined heterozygosity for the causative mutations, whereas monoallelic mutations lead to hypofibrinogenemia. The bleeding phenotype varies in accordance with fibrinogen levels, ranging generally from frequent and often life-threatening bleeding in afibrinogenemia to the absence of symptoms, or mild bleeding symptoms in mild hypofibrinogenemia. The main treatment for quantitative fibrinogen disorders is fibrinogen supplementation. Despite low fibrinogen levels, a tendency for thrombosis is a characteristic of these disorders and may be exacerbated by fibrinogen supplementation. The management of surgery and pregnancy presents significant challenges regarding the amount of fibrinogen replacement and the need for thromboprophylaxis. The objective of this article is to present 4 clinical scenarios that illustrate common clinical challenges and to propose strategies for managing bleeding, thrombosis, surgery, and pregnancy.