The pathogenesis of multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS) is linked to an aging immune system. Chronic activation of B/plasma cells may contribute to the origin of MGUS, which is frequent in the older individuals. However, only 1% of individuals with MGUS annually experience progression to MM. The immune system can specifically recognize MGUS lesions, and preclinical MM models provide evidence for both innate and adaptive immune surveillance. Multiomic studies have identified several systemic alterations at the MGUS stage, suggesting accelerated immune aging prior to evolution into clinical malignancy. MM is further associated with spatial alterations in patterns of tumor growth and in situ regulation of regional immunity. Both tumor and microenvironment-related factors contribute to immune paresis, which facilitates the dissemination of clonal plasma cells, and increases the risk of infections in patients with MM. Immune profiles in blood or marrow exhibit considerable heterogeneity, and have been linked to outcomes following immune therapies, including T-cell redirection. Understanding how underlying systemic immune changes impact in vivo function and durability of natural or synthetic tumor/antigen-specific immunity needs further study. Preserving or restoring immune function may be critical for long-term outcomes both in the context of prevention of clinical MM and of treating active disease. Benchmarking of immune biomarkers followed by its prospective integration into current risk models, together with improved understanding of mechanisms underlying tumor immunity in vivo, are needed to optimize immune approaches and improve outcomes in MM.

Although allogeneic hematopoietic stem cell transplantation is a leading treatment approach for myeloid malignancies, challenges in its immune biology and in treatment approaches remain. In the past decade, major advances in the knowledge of mechanisms of graft-versus-host disease (GVHD) has allowed development of new treatments both for GVHD prophylaxis and treatment. However, although successes did occur, failure did as well. Reasons for failure can be linked either to incomplete understanding of the pathophysiology of GVHD, or, in some cases, to errors in the design of clinical trials. Better GVHD prophylaxes and disease control have likely led to decreased nonrelapse mortality (NRM). However, although NRM rates have decreased, rates of relapse of the original malignancy have not significantly improved. Our current understanding of the biology of the graft-versus-leukemia (GVL) effect still lags behind that of GVHD, and treatment approaches to manipulate the GVL effect remain limited. The reasons for such a lag are numerous, but improved knowledge of the biology of hematological malignancies open the gate to new developments, providing that we can better understand the interplay between the immune system with leukemic clones. From a therapeutical perspective, much attention has been paid to the results from randomized clinical trials and from a biological perspective on recent discoveries, especially in the human setting. The objective of this perspective is to analyze what are the current challenges in the biology and treatment of GVHD and GVL and to provide a personal view on how some biological and therapeutic issues could be approached.

Chronic lymphocytic leukemia (CLL) is a disease of great clinical and biologic heterogeneity; some patients are observed for years without symptoms, whereas others rapidly develop progressive disease requiring treatment. With therapy, some patients eventually develop resistant CLL or transformation to an aggressive form. Across this spectrum, patients experience immune dysfunction associated with increased risk for infection and second cancers, contributing to morbidity and mortality of the disease. The ultimate therapeutic bull's-eye for CLL is to eliminate the disease and achieve immune restoration. Disease elimination can potentially be achieved for a fraction of patients treated first line with chemoimmunotherapy (fludarabine, cyclophosphamide, and rituximab), for some patients who receive time-limited combined targeted therapy, and for some patients with relapsed/refractory CLL who undergo allogeneic stem cell transplant. Long-term immune restoration for these patients is elusive. Current targeted therapies, including Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors and CD20 monoclonal antibodies used in combinations, can produce exceptional therapeutic outcomes, which are improving survival for patients who need treatment. Although clear progress has been made toward highly effective CLL management, appreciation of the full impact of these advances will require time because of the chronic nature of the disease. In addition, it is imperative to ensure global access to the targeted therapies, emphasizing the need for harmonized regulatory oversight and affordable treatment options worldwide. Here, we discuss research and collaborative strategies to refine the use of targeted agents to eliminate CLL and restore immune function for all affected individuals.

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.

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.

"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.

Phosphoinositide 3-kinase gamma (PI3Kγ), the only class IB PI3 kinase, is a cell-extrinsic immunotherapy target in solid tumors. PI3Kγ inhibition reprograms immunosuppressive myeloid cells to acquire immunostimulatory phenotypes, which promote antitumor cytotoxic T-cell activity. Although PI3Kγ inhibition has no direct effect on solid tumor cells, several new studies have nominated PI3Kγ as a cell-intrinsic target in various leukemias, particularly acute myeloid leukemia. Intrinsic dependency on PI3Kγ is present at baseline in leukemias with specific pathological characteristics, is inducible by extrinsic inflammation in others, and may also be acquired with resistance to certain therapies. The discovery of leukemia PI3Kγ dependency has generated enthusiasm for immediate clinical trial evaluation of inhibitor monotherapy and combinations. Parallel laboratory evaluation is needed to develop an improved understanding of leukemia disease features associated with clinical inhibitor sensitivity that might suggest biomarker-directed patient enrichment strategies. In this review, we discuss recent progress credentialing PI3Kγ as a bona fide target in leukemia. We also highlight open questions, including a need to understand the mechanism of acquired resistance to PI3Kγ inhibition, how to optimally prioritize combination therapies to enhance PI3Kγ inhibitor utility, and how cell-extrinsic effects of PI3Kγ inhibition in the leukemia microenvironment might also contribute to clinical activity.

Tyrosine kinase inhibitors (TKIs) are the mainstay of treatment for patients with chronic myeloid leukemia. The standard dose has been established for each drug according to the indication for the various stages of the disease and whether as initial therapy or after failure of previous therapies. The recommended doses are fixed for all patients and dose adjustments are mostly recommended for management of adverse events. The standard doses have been derived largely from phase 1 studies, but as we discuss in this review, the current model may not be optimal for this purpose for drugs such as TKIs that are meant to be used for extended periods of time. Subsequent studies have led to changes in the initial recommendations for some drugs. In others, experience and real-world data have led to the use of TKIs using doses and adjustments that may be different than what clinical trials have recommended. In other scenarios, available data suggest that the current standard dose may need to be revisited. It may also be time to reconsider the standard approach of starting therapy with the standard dose and adjusting merely based on adverse events. We propose a flexible model that perhaps reflects more accurately what is being done frequently in the clinic.

Inherited bone marrow failure syndromes (IBMFS) are genetic disorders of impaired hematopoiesis that manifest in childhood with both cytopenias and extrahematologic findings. Although several IBMFS are categorized as ribosomopathies owing to shared underlying ribosomal dysfunction, there is a broader disruption of the protein homeostasis (proteostasis) network across both classic and emerging IBMFS. Precise regulation of the proteostasis network, including mechanisms of protein synthesis, folding, trafficking, and degradation and associated stress response pathways, has emerged as essential for maintaining hematopoietic stem cell function, providing new potential mechanistic insights into IBMFS pathogenesis. Furthermore, the varied clinical trajectories of patients with IBMFS with possible divergent outcomes of malignancy and spontaneous remission may reflect developmental and temporal changes in proteostasis activity and be driven by strong selective pressures to restore proteostasis. These new insights are spurring fresh therapeutic approaches to target proteostasis. Thus, further evaluation of proteostasis regulation and the consequences of proteostasis disruption in IBMFS could aid in developing new biomarkers, therapeutic agents, and preventive approaches for patients.

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.

Immune cell functionality is highly dependent on the actin cytoskeleton. The actin cytoskeleton is regulated by a complex molecular machinery that involves multiple genes. Mutations in these genes can cause inborn errors of immunity, also termed immunoactinopathies, of which Wiskott-Aldrich syndrome is the best-characterized entity. Currently, mutations in 23 genes can be considered causative of immunoactinopathies. Immunoactinopathies are rare disease entities with complex combinations of clinical manifestations, including immunodeficiency, immune dysregulation, malignancies, atopy, thrombocytopenia and bleeding, skin involvement, or congenital defects. Prompt diagnosis is crucial, because hematopoietic stem cell transplantation in an early phase can offer cure and prevent further complications. This review provides a detailed summary of the clinical experience with immunoactinopathies so far, elaborates on the most distinguishing features of immunoactinopathies by providing a clinical categorization, and links this information to the underlying biological pathways. This information may be of help to clinicians in the diagnosis of patients and to eventually improve patient care.

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?