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.

The advent of chimeric antigen receptor (CAR) T cells has revolutionized the treatment landscape for hematologic malignancies, and emerging evidence suggests their potential in autoimmune diseases (AIDs). This article evaluates the early successes and future implications of B-cell-targeting CAR T-cell therapy in AIDs. Initial applications, particularly in refractory systemic lupus erythematosus, have demonstrated significant and durable clinical remissions, with accompanying evaluation of the immune system suggesting a so-called "reset" of innate inflammation and adaptive autoimmunity. This has generated widespread interest in expanding this therapeutic approach. CAR T cells offer unique advantages over other treatment modalities, including very deep B-cell depletion and unique therapeutic activity within inflamed tissues and associated lymphoid structures. However, the field must address key concerns, including long-term toxicity, particularly the risk of secondary malignancies, and future accessibility given the higher prevalence of AIDs compared with malignancies. Technological advances in cell therapy, such as next-generation CAR T cells, allogeneic off-the-shelf products, and alternative cell types, such as regulatory CAR T cells, are being explored in AIDs to improve efficacy and safety. In addition, bispecific antibodies are emerging as potential alternatives or complements to CAR T cells, potentially offering comparable efficacy without the need for complex logistics, lymphodepletion, and the risk of insertional mutagenesis. As the field evolves, cellular therapists will play a critical role in the multidisciplinary teams managing these complex cases. The transformative potential of CAR T cells in AIDs is undeniable, but careful consideration of safety, efficacy, and implementation is essential as this novel therapeutic approach moves forward.

Acute myeloid leukemia (AML) remains a dismal disease with poor prognosis, particularly in the relapsed/refractory (R/R) setting. Chimeric antigen receptor (CAR) therapy has yielded remarkable clinical results in other leukemias and thus has, in principle, the potential to achieve similar outcomes in R/R AML. Redirecting the approved CD19-specific CAR designs against the myeloid antigens CD33, CD123, or CLEC12A has occasionally yielded morphologic leukemia-free states but has so far been marred by threatening myeloablation and early relapses. These safety and efficacy limitations are largely due to the challenge of identifying suitable target antigens and designing adequate receptors for effective recognition and safe elimination of AML. Building on lessons learned from the initial clinical attempts, a new wave of CAR strategies relying on alternative target antigens and innovative CAR designs is about to enter clinical evaluation. Adapted multiantigen targeting, logic gating, and emerging cell engineering solutions offer new possibilities to better direct T-cell specificity and sensitivity toward AML. Pharmacologic modulation and genetic epitope engineering may extend these approaches by augmenting target expression in AML cells or minimizing target expression in normal hematopoietic cells. On/off switches or CAR T-cell depletion may curb excessive or deleterious CAR activity. Investigation of AML-intrinsic resistance and leukemic microenvironmental factors is poised to reveal additional targetable AML vulnerabilities. We summarize here the findings, challenges, and new developments of CAR therapy for AML. These illustrate the need to specifically adapt CAR strategies to the complex biology of AML to achieve better therapeutic outcomes.

Macrophages execute core functions in maintaining tissue homeostasis, in which their extensive plasticity permits a spectrum of functions from tissue remodeling to immune defense. However, perturbations to tissue-resident macrophages during disease, and the subsequent emergence of monocyte-derived macrophages, can hinder tissue recovery and promote further damage through inflammatory and fibrotic programs. Gaining a fundamental understanding of the critical pathways defining pathogenic macrophage populations enables the development of targeted therapeutic approaches to improve disease outcomes. In the setting of chronic graft-versus-host disease (cGVHD), which remains the major complication of allogeneic hematopoietic stem cell transplantation, colony-stimulating factor 1 (CSF1)-dependent donor-derived macrophages have been identified as key pathogenic mediators of fibrotic skin and lung disease. Antibody blockade of the CSF1 receptor (CSF1R) to induce macrophage depletion showed remarkable capacity to prevent fibrosis in preclinical models and has subsequently demonstrated impressive efficacy for improving cGVHD in ongoing clinical trials. Similarly, macrophage depletion approaches are currently under investigation for their potential to augment responses to immune checkpoint inhibition. Moreover, both monocyte and tissue-resident macrophage populations have recently been implicated as mediators of the numerous toxicities associated with chimeric antigen receptor T-cell therapy, further highlighting potential avenues of macrophage-based interventions to improve clinical outcomes. Herein, we examine the current literature on basic macrophage biology and contextualize this in the setting of cellular and immunotherapy. Additionally, we highlight mechanisms by which macrophages can be targeted, largely by interfering with the CSF1/CSF1R signaling axis, for therapeutic benefit in the context of both cellular and immunotherapy.

Follicular lymphoma (FL) usually requires multiple lines of therapy, and disease control remains largely insufficient with conventional chemoimmunotherapy. Several T-cell-redirecting strategies recently approved in the relapsed/refractory setting have the potential to improve outcomes and change the treatment algorithm in FL. This review focuses on the role of chimeric antigen receptor T cells and bispecific antibodies in FL, paying special attention to sequencing approaches and future directions.

Anemia is the most prevalent cytopenia in lower-risk myelodysplastic neoplasms (LR-MDS). There is a paucity of drugs for red blood cell transfusion dependence (RBC-TD), and erythropoiesis-stimulating agents (ESAs) are the mainstay of therapy in many centers. Imetelstat, an oligonucleotide telomerase inhibitor, was recently approved for adults with RBC-TD LR-MDS who are ineligible for or failed prior ESA therapy. Although not yet approved worldwide, here we spotlight the current data for imetelstat and where it may fit in the therapeutic landscape of LR-MDS.

Long-term outcomes with tyrosine kinase inhibitors (TKIs) show that their impact on chronic myeloid leukemia (CML) is sustained as shown by 13 studies with 5- to 14-year-follow-up, and numerous shorter-term studies of newly diagnosed chronic-phase CML. Twenty-five years of imatinib (IM) treatment confirm its beneficial effect on survival and possible cure of CML. Large, randomized, academic, treatment-optimization studies have confirmed and extended the pivotal International Randomized Study on Interferon and STI571. The 3 academic trials in Germany, France, and the United Kingdom did not show benefit of the IM-interferon (IFN) combination, despite the immunomodulatory properties of IFN. Second-generation (2G) TKIs induce responses faster than IM and recognize IM-resistance mutations but do not prolong survival compared with IM. Adverse drug-related reactions (ADRs) limit the general use of 2GTKIs despite frequent but mostly mild IM-ADRs. Molecular monitoring of treatment efficacy has been established serving as an example for other neoplasms. Comorbidities, transcript type, and the negative impact of high-risk additional chromosomal abnormalities were addressed. A new prognostic score (European Treatment and Outcome Study long-term survival score) accounts for the fact that the majority of patients with CML die of other causes. Non-CML determinants of survival have been identified. Large and long-term observational studies demonstrate that progress with CML management has also reached routine care in most but not all instances. Despite merits of 2GTKIs, IM remains the preferred treatment option for CML because of its efficacy and superior safety.

BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies that are caused by the proliferation of myeloid cells that harbor a JAK-STAT pathway activating driver mutation. MPN management recommendations are based on the evaluation of different risks to prevent disease evolution-associated events while preserving patients' quality of life. Such risks can be common across all MPNs or specific to each subtype (polycythemia vera [PV], essential thrombocythemia [ET], prefibrotic myelofibrosis [MF], and primary MF). Patients with MF harbor the worse prognosis, and hematopoietic stem cell transplantation (HSCT) is the only curative treatment at the expense of a high rate of morbidity and mortality. Therefore, accurate scoring systems to estimate overall survival are crucial for the management of patients with MF and the selection for HSCT. In PV and ET, the prediction of vascular events is prioritized given their higher incidence and related morbidity and mortality. Finally, quality of life evaluation is important for all subtypes. To predict these risks and adapt MPN therapeutic strategies, clinical risk scores have been developed over the past decades and more recently have incorporated molecular risk factors for more accurate risk stratification. The large number of scoring systems available, combined with disease heterogeneity and the necessity to predict diverse outcomes, make it difficult for clinicians to choose the most appropriate score to evaluate their patients' risk in 2024. Here, we provide an overview of MPN disease evolution-associated event incidence and conduct an exhaustive comparative review of the scoring systems currently available for each risk. Finally, we propose an algorithm for the use of these scores in clinical practice in each MPN subtype.

Sterile alpha motif domain-containing protein 9 (SAMD9) and SAMD9-like (SAMD9L) are paralogous genes encoding antiviral proteins that negatively regulate cell proliferation. Heterozygous germ line gain-of-function (GoF) SAMD9/9L variants cause multisystem syndromes with variable manifestations. The unifying features are cytopenia, immunodeficiency, infections, bone marrow failure, myelodysplasia, and monosomy 7. Nonhematopoietic presentations can affect almost every organ system. Growth impairment and adrenal insufficiency are typical in SAMD9, whereas progressive neurologic deficits characterize SAMD9L. Most patients (>90%) carry germ line missense GoF variants. A subgroup of patients presenting with SAMD9L-associated inflammatory disease carry frameshift-truncating variants that are also GoF. Somatic genetic rescue occurs in two-third of patients or more and involves monosomy 7, which may spontaneously disappear (transient monosomy 7) or progress to myelodysplastic syndrome (MDS)/leukemia, and adaptive clones with somatic SAMD9/9L compensatory mutations or uniparental disomy 7q (UPD7q), both associated with remission. This manuscript examines the clinical and genetic spectrum, therapies, and outcome based on 243 published patients compiled in our registry, with additional genetic information on 62 unpublished cases. We consolidate the diverse clinical manifestations and diagnostic challenges of SAMD9/9L syndromes to enhance recognition and improve patient care. We highlight the knowledge gaps in pathomechanisms and emphasize the importance of genetic surveillance assessing disease remission vs disease progression. Insights are provided into variant curation and the necessity of testing for somatic SAMD9/9L mutations and UPD7q. Multidisciplinary care in specialized centers is critical to manage these complex disorders. Future natural history studies, especially in patients with monosomy 7, will help formulate evidence-based surveillance protocols and optimize transplant timing and outcomes.

Both the 2022 World Health Organization Classification of Hematolymphoid Tumors, 5th Edition and the International Consensus Classification of lymphoma have refined the way we now approach high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements moving the previous generation of classification a step forward. The unifying biology of MYC/BCL2 tumors has become clearer and their inferior prognosis confirmed compared with those with morphologic similar phenotypes but lacking the classifcation defining cytogenetic abnormalities. Fluorescent in situ hybridization testing has now become largely population based, and we have learned much from this. We can readily define molecular categories and apply these widely to clinical practice. Uncertainty has, however, been shed on the place of MYC/BCL6 translocations in defining a common disease group of double hit lymphoma due to biological heterogeneity. We have enhanced our knowledge of outcomes and the role of therapy intensification to overcome chemotherapy resistance in HGBL. For those patients failed by initial induction chemotherapy, immunotherapy approaches, including chimeric antigen receptor T-cell therapies, are improving outcomes. Novel inhibitors, targeting dysregulated oncogenic proteins, are being explored at pace. The rare, but difficult, diagnostic classification HGBL (not otherwise specified) remains a diagnosis of exclusion with limited data on an optimal clinical approach. The days of talking loosely of double- and triple-hit lymphoma are numbered as biology and outcomes may not be shared. This review synergizes the current data on biology, prognosis, and therapies in HGBL.

The US Food and Drug Administration announcement in November 2023 regarding reports of the occurrence of secondary T-cell lymphomas in patients receiving chimeric antigen receptor T cells (CAR-Ts) for B-cell malignancies resulted in widespread concern among patients, clinicians, and scientists. Little information relevant to assessing causality, most importantly whether CAR retroviral or lentiviral vector genomic insertions contribute to oncogenesis, was initially available. However, since that time, several publications have provided clinical and molecular details on 3 cases showing clonal CAR vector insertions in tumor cells but without firm evidence these insertions played any role in oncogenic transformation. In addition, several other cases have been reported without vector detected in tumor cells. In addition, epidemiologic analyses as well as institutional long-term CAR-T recipient cohort studies provide important additional information suggesting the risk of T-cell lymphomas after CAR-T therapies is extremely low. This review will provide a summary of information available to date, as well as review relevant prior research suggesting a low susceptibility of mature T cells to insertional oncogenesis and documenting the almost complete lack of T-cell transformation after natural HIV infection. Alternative factors that may predispose patients treated with CAR-Ts to secondary hematologic malignancies, including immune dysfunction and clonal hematopoiesis, are discussed, and likely play a greater role than insertional mutagenesis in secondary malignancies after CAR therapies.

Despite advancements in new treatments, management of older patients with acute lymphoblastic leukemia (ALL) remains an unmet medical need. With increasing age, patients with ALL have a significantly lower complete remission rate, higher early mortality and relapse rate, and poorer survival than younger patients. This is attributed to a higher prevalence of adverse prognostic factors among older individuals and reduced tolerance to chemotherapy. Progress has been made in tailoring moderately intensive chemotherapy protocols for Philadelphia chromosome (Ph)/BCR::ABL-negative ALL in older patients, and recent phase 2 studies have explored integrating immunotherapy into initial treatment with very promising results. However, establishing new standard regimens for this age group remains and improving general management strategy is a pending task.

Outcomes for acute myeloid leukemia (AML) have improved significantly in the past decade with the approval of novel therapeutics targeting diverse vulnerabilities of leukemic cells, expanded access to stem cell transplantation, and improved safety of transplantation. Although attainment of initial remission is now an expected outcome in most patients with AML receiving intensive or nonintensive induction regimens, maintaining long-term remission and decreasing the risk of relapse remain critical challenges. Maintenance approaches using assorted agents have yielded variable success and only recently have been integrated to the standard of care. We present 4 commonly encountered clinical scenarios that highlight challenges facing physicians as they care for patients with AML in remission and contemplate using postremission maintenance. Using published studies and emerging clinical data, we discuss our approach to maintenance treatment in AML, emphasizing that selection of a specific strategy is an individualized decision based on leukemia biology and risk stratification, presence of targetable mutations, initial treatment approach, performance status, and feasibility of allogeneic stem cell transplantation.

Cardiorespiratory complications after blood transfusion are the leading cause of transfusion-related morbidity and mortality worldwide. Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) are the 2 most frequently reported cardiorespiratory complications, both of which have clear pathophysiology-based treatment algorithms. In the past decades, translational research has increased understanding of mechanisms in place, including patient and transfusion risk factors. This has led to updated international definitions, biomarker-based diagnostics, interventions, and risk mitigation measures. Preventive measures have led to a significant reduction in TRALI, and TACO prevention is increasingly highlighted within hemovigilance. In this article, clinical case scenarios illustrate the challenges of diagnosing, treating, and finally classifying cardiorespiratory complications of transfusion. A background on current definitions, diagnostics, and pathophysiological mechanisms will be given, as well as how to deal with cases in which TRALI and TACO are both present. Hemovigilance systems worldwide are essential to provide insight into the incidence of transfusion complications. Furthermore, these systems provide a basis to discover new patient and transfusion risk factors and to better balance the down- and upside of a transfusion for a patient. Finally, we discuss the future challenges and research priorities in the field of cardiorespiratory transfusion-related complications.

Cure rates for patients with acute lymphoblastic leukemia (ALL) have improved markedly in recent decades, in part because of risk stratification incorporating leukemia genomics, response to treatment, and clinical features to be able to determine at diagnosis which patients are more likely to relapse or have refractory disease. Although risk stratification is well developed for patients with B-lineage ALL, it remains challenging for those with T-lineage ALL (T-ALL). Prognostic factors validated across clinical trials and real-world data in T-ALL include age, central nervous system involvement, and measurable residual disease (MRD) response. Immunophenotype, including early T-cell precursor ALL, is widely used to classify T-ALL but is not consistently associated with outcome in multivariable risk models. Historically, few genetic alterations have been consistently associated with outcome, but recent comprehensive, large-scale genomic profiling has identified multiple genetic subtypes and alterations associated with outcome independent of MRD. This review highlights ongoing efforts to identify reliable prognostic biomarkers and underscores the potential of genomics-based classification to guide future T-ALL treatment strategies.

Platelets play crucial roles in hemostasis, thrombosis, and immunity, but our understanding of their complex biogenesis (thrombopoiesis) is currently incomplete. Deeper insight into the mechanisms of platelet biogenesis inside and outside the body is fundamental for managing hematological disorders and for the development of novel cell-based therapies. In this article, we address the current understanding of in vivo thrombopoiesis, including mechanisms of platelet generation from megakaryocytes (proplatelet formation, cytoplasmic fragmentation, and membrane budding) and their physiological location. Progress has been made in replicating these processes in vitro for potential therapeutic application, notably in platelet transfusion and bioengineering of platelets for novel targeted therapies. The current platelet-generating systems and their limitations, particularly yield, scalability, and functionality, are discussed. Finally, we highlight the current controversies and challenges in the field that need to be addressed to achieve a full understanding of these processes, in vivo and in vitro.