Diffuse large B-cell lymphoma (DLBCL) is an aggressive, yet curable, malignancy, but older patients are at higher risk of relapsed disease because they may not be eligible for full-intensity frontline chemoimmunotherapy or have comorbidities that limit standard treatments. Recent years have brought more treatment options than ever for this patient population, but it remains challenging to determine which can be safely and effectively offered to older patients. Formal determinations of fitness including geriatric assessments remain critical, but there is less guidance on how to best use this tool in the relapsed setting. Chimeric antigen receptor T-cell therapy is accessible to older patients, provided they can be supported through the intensive road to this treatment. If relapse occurs despite this or alternative therapies are preferred, many novel therapeutic options and combinations exist with some potential modifications for older adults, such as bispecific antibodies, tafasitamab and lenalidomide, polatuzumab-containing regimens, or loncastuximab tesirine. This article provides a summary of our approach to the management of this diverse population of older patients with relapsed or refractory DLBCL.

Secondary acute myeloid leukemia (sAML) has traditionally been used to designate any AML disease arising from an antecedent hematologic disorder or after prior cytotoxic or radiation therapy. We now know sAML comprises multiple disease entities with distinct clinical and biological features: AML, myelodysplastic related; myeloproliferative neoplasm-blast phase; and AML post-cytotoxic therapy. These entities largely represent adverse-risk phenotypes with the majority of patients experiencing suboptimal outcomes with standard therapeutic options. Given the aging general population and the increased life span of individuals receiving DNA-damaging agents for other medical conditions, the incidence of these diseases is steadily rising and now comprise ∼25% to 30% of all new AML diagnoses. Despite the plethora of novel agents approved for AML since 2017, many either are not applicable to sAML (ie, lacking a targetable mutation), have limited efficacy, or have not been studied in these specific entities. Furthermore, these patients are underrepresented in clinical trials, and novel therapeutic options are critically needed. Here, we present multiple patient cases exemplifying the new nomenclature and classification of the diseases comprising sAML and highlighting their diverse presentations. We provide our therapeutic approach for each clinical scenario and discuss the challenges of treatment with the currently available armamentarium.

Venetoclax (VEN) received full approval in October 2020 for use in older patients who are unfit with acute myeloid leukemia (AML) combined with either hypomethylating agents or low-dose cytarabine. This ended a semicentennial of stalled clinical progress and initiated a new treatment option with proven capacity to enhance response and prolong survival in older patients with AML. Despite widespread use of azacitidine-VEN (AZA-VEN), there is increasing appreciation that this regimen is myelosuppressive and associated with a higher risk of infectious complications than AZA alone. Key principles of initial management include prevention of tumor lysis syndrome in patients at high risk and minimizing infectious complications during induction. In the postremission phase, limiting cumulative marrow suppression by allowing sufficient time between cycles for optimal marrow recovery and truncating the duration of VEN exposure for those with delayed blood count recovery have emerged as important axioms of effective care. This article casts a clinical spotlight on important challenges and dilemmas encountered in practice. We also outline a structured framework to assist in the safe management of AZA-VEN in the clinic.

At least 25% to 35% of patients with large B-cell lymphoma (LBCL) are not cured with frontline treatment, with generally poor subsequent outcomes. This motivates ongoing and intense interest in improving the frontline treatment of this disease. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has remained the standard of care for 20 years despite dozens of trials aiming to improve upon this regimen, and only recently has a novel regimen (pola-R-CHP [polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone]) challenged its supremacy. Fortunately, at least 15 promising randomized trials evaluating new treatments in frontline LBCL treatment are underway. They differ not only in the therapy evaluated in the experimental arm, but in the choice of control arm, primary end point, and patient selection strategy, with some targeting specific biologic subtypes, some focusing on specific high-risk patient populations, and others enrolling older or frail patients. Novel response-adapted strategies leveraging circulating tumor DNA are also underway. Although this variety of approaches provides a welcome increase in the overall likelihood of success, it will also present challenges if several of these trials are successful and we must choose among multiple potential treatment options that were not all tested in the same fashion. In this review, we summarize the main ongoing frontline randomized trials and discuss some of the questions that we will face in interpreting and applying their results in clinical practice in the next few years.

Chimeric antigen receptor T-cell therapy (CAR-T) targeting CD19 has transformed the management of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), with the US Food and Drug Administration approval of tisagenlecleucel for pediatric/young adult patients and brexucabtagene autoleucel for adults. Efficacy is contingent upon several factors including disease burden. Emerging data suggest that bridging therapy, lymphodepletion, and, for some patients, consolidation therapy have an important role in the success of treatment. Furthermore, strategies to define and manage immunotoxic side effects including hematotoxicity is critical to safe delivery. Advancements in CAR-T design beyond CD19 represent an ongoing therapeutic evolution. Overall, CAR-T signifies a paradigm shift in B-ALL management, with the potential for improved remission and survival in a historically challenging patient population.

Before the advent of effective iron chelation, death from iron-induced cardiomyopathy and endocrine failure occurred in the second decade in patients with thalassemia major, and this experience has driven expectation of poor outcomes and caused anxiety in all disorders associated with iron loading to this day. To be clear, severe iron overload still causes significant morbidity and mortality in many parts of the world, but current understanding of iron metabolism, noninvasive monitoring of organ-specific iron loading in humans, and effective iron chelators have dramatically reduced morbidity of iron overload. Furthermore, clinical experience in hemoglobinopathies supports iron biology learned from animal studies and identifies common concepts in the biology of iron toxicity that inform the management of iron toxicity in several human disorders. The resultant significant increase in survival uncovers new complications due to much longer exposure to anemia and to iron, which must be considered in long-term therapeutic strategies. This review will discuss the management of iron toxicity in patients with hemoglobinopathies and transfusion-dependent anemias and how iron biology informs the clinical approach to treatment.

Although complete remission rates in adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have improved over the last 2 decades, it is still inferior to that of the pediatric population, and once in remission, the risk of relapse is still high. Furthermore, although pediatric-inspired chemotherapy regimens have improved long-term outcomes for adolescents and young adults, these intensive chemotherapy regimens are not well tolerated in older patients and are associated with higher morbidity and mortality. Immunotherapeutic agents offer a potential opportunity to improve response and decrease relapse without increasing toxicity. The incorporation of rituximab (anti-CD20 monoclonal antibody) into chemotherapy regimens has been shown to improve outcomes. The treatment of BCP-ALL in adults has been transformed with the approval of inotuzumab ozogamicin (anti-CD22 antibody-drug conjugate), blinatumomab (CD3/CD19 bispecific antibody construct), and chimeric antigen receptor T cells for relapsed or refractory disease and of blinatumomab for measurable residual disease (MRD)-positive remission. More recently, studies of inotuzumab and blinatumomab have shown promising results when used up front either with or without multiagent chemotherapy. Blinatumomab has also been shown in a randomized trial to provide a survival benefit in patients with MRD-negative first remission when added to chemotherapy, which recently led to its additional US Food and Drug Administration approval for use in consolidation. In this review, we highlight the evolution of chemoimmunotherapy-based treatment approaches in the management of treatment-naïve BCP-ALL.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of patients with relapsed or refractory hematologic malignancies, but it comes with unique toxicities, notably cytokine release syndrome and ICANS (immune effector cell-associated neurotoxicity syndrome). As experience with CAR T-cell therapy grows, distinct and infrequent neurologic complications are becoming increasingly evident. Recently, reports of acute myelopathy after the administration of CAR T-cell therapies have been accumulating. Despite the establishment of consensus guidelines for managing ICANS, there remains limited guidance on the appropriate investigations and treatments for this rare complication. In this manuscript, we delve into the clinical features, pathophysiology, and strategies for the optimal management of acute myelitis after CAR T-cell therapy and draw insights from reported cases in the literature.

Peripheral T-cell lymphomas (PTCLs) encompass a heterogeneous group of postthymic T-cell lymphomas with >30 distinct subtypes associated with varied clinicopathological features. Unfortunately, the overall survival of the major PTCL subtypes is dismal and has not improved for decades; thus, there is an urgent unmet clinical need to improve diagnosis, therapies, and clinical outcomes. The diagnosis is often challenging, requiring a combinatorial evaluation of clinical, morphologic, and immunophenotypic features. PTCL pathobiology is difficult to investigate due to enormous intertumor and intratumor heterogeneity, limited tissue availability, and the paucity of authentic T-cell lymphoma cell lines or genetically faithful animal models. The application of transcriptomic profiling and genomic sequencing has markedly accelerated the discovery of new biomarkers, molecular signatures, and genetic lesions, and some of the discoveries have been included in the revised World Health Organization or International Consensus Classification. Genome-wide investigations have revealed the mutational landscape and transcriptomic profiles of PTCL entities, defined the cell of origin as a major determinant of T-cell lymphoma biology, and allowed for the refinement of biologically and clinically meaningful entities for precision therapy. In this review, we prioritize the discussion on common nodal PTCL subtypes together with 2 virus-associated T-cell and natural killer cell lymphomas. We succinctly review normal T-cell development, differentiation, and T-cell receptor signaling as they relate to PTCL pathogenesis and biology. This review will facilitate a better biological understanding of the different PTCL entities and their stratification for additional studies and target-directed clinical trials.

The Philadelphia (Ph) chromosome is one of the few genetic aberrations in which a casualty has been proven and, as such, represents a success in the history of medicine. This is also evident in the setting of Ph+ acute lymphoblastic leukemia (ALL), the most frequent genetic subgroup in adult ALL, whose incidence increases with age and whose prognosis, before the advent of tyrosine kinase inhibitors (TKIs), was particularly poor. The outcome and management of patients with Ph+ ALL have greatly improved since the incorporation of first-, second-, and third-generation TKIs in the therapeutic backbone and is further changing with the more recent introduction of immunotherapy. This allows for long-term survival rates currently ranging between 75% and 80%. The clinical scenario of adult Ph+ ALL has thus changed profoundly, and new challenges are emerging. In this article, illustrative clinical cases are used to discuss the current role of systemic chemotherapy and allogeneic stem cell transplant, the difficulty in treating central nervous system relapses and, more in general, relapses in the current therapeutic era, and the possibility of stopping TKIs. Finally, the challenges related to an optimal management of these patients are discussed.

The microbiota, comprising bacteria, fungi, and viruses residing within our bodies, functions as a key modulator in host health and states, including immune responses. Studies have linked microbiota and microbiota-derived metabolites to immune cell functions. In this review, we probe the complex relationship between the human microbiota and clinical outcomes of cellular therapies that leverage immune cells to fight various cancers. With a particular emphasis on hematopoietic cell transplantation and chimeric antigen receptor T-cell therapy, we explore the potential mechanisms underpinning this interaction. We also highlight the interventional applications of the microbiota in cellular therapy while outlining future research directions in the field.

Coagulation factor VIII (FVIII) is essential for hemostasis. After activation, it combines with activated FIX (FIXa) on anionic membranes to form the intrinsic Xase enzyme complex, responsible for activating FX in the rate-limiting step of sustained coagulation. Hemophilia A (HA) and hemophilia B are due to inherited deficiencies in the activity of FVIII and FIX, respectively. Treatment of HA over the last decade has benefited from an improved understanding of FVIII biology, including its secretion pathway, its interaction with von Willebrand factor in circulation, the biochemical nature of its FIXa cofactor activity, the regulation of activated FVIII by inactivation pathways, and its surprising immunogenicity. This has facilitated biotechnology innovations with first-in-class examples of several new therapeutic modalities recently receiving regulatory approval for HA, including FVIII-mimetic bispecific antibodies and recombinant adeno-associated viral (rAAV) vector-based gene therapy. Biological insights into FVIII also guide the development and use of gain-of-function FVIII variants aimed at addressing the limitations of first-generation rAAV vectors for HA. Several gain-of-function FVIII variants designed to have improved secretion are currently incorporated in second-generation rAAV vectors and have recently entered clinical trials. Continued mutually reinforcing advancements in the understanding of FVIII biology and treatments for HA are necessary to achieve the ultimate goal of hemophilia therapy: normalizing hemostasis and optimizing well-being with minimal treatment burden for all patients worldwide.

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that is clinically characterized by its heterogeneous behavior, with courses ranging from indolent to highly aggressive cases with limited prognosis. Targeted treatment alternatives in first-line and relapse settings are more and more shaping the therapeutic landscape of MCL. The development and implementation of new targeted and immunotherapeutic approaches have already improved outcomes for patients with MCL with refractory or relapsed disease. However, long-term prognosis is still limited, and patients with relapsed/refractory (R/R) disease, especially those failing Bruton tyrosine kinase (BTK) inhibitor treatment, usually have a dismal outcome. This review summarizes the current and emerging treatment options for R/R MCL, focusing on the implementation of combined targeted treatment strategies such as BTK inhibitors and BCL2 inhibitors, as well as immune-therapeutic approaches including chimeric antigen receptor T cells and bispecific antibodies.

Despite significant advancements in single-antigen targeted therapies for B-cell acute lymphoblastic leukemia (B-ALL), nonresponse and relapse persist as major challenges. Antigen escape after blinatumomab or CD19-directed chimeric antigen receptor (CAR) T cells (CD19-CAR), as CD19-negative B-ALL or lineage switch (LS) to acute myeloid leukemia, present diagnostic and treatment complexities. Given the poor outcomes for patients experiencing a postinfusion relapse, particularly those with loss of the target antigen, a strategic approach to diagnosis and treatment is imperative. In this discussion, we outline a systematic approach to managing postimmunotherapy events, categorized by CD19-positive relapse, CD19-negative relapse, and LS. We explore treatment modalities including CD19-CAR reinfusions, humanized CAR constructs, combinatorial strategies, and alternative antigen-targeted therapies, such as blinatumomab and inotuzumab. Challenges in diagnosis, particularly with antigen-escape, are addressed, highlighting the role of next-generation sequencing and multiparameter flow cytometry for myeloid marker monitoring.

The fifth edition of the World Health Organization (WHO) classification and the International Consensus Classification (ICC) both include a category "myeloid/lymphoid neoplasms (MLN) with eosinophilia (eo) and tyrosine kinase (TK) gene fusions" (WHO, MLN-TK; ICC, M/LN-eo-TK). This rare group comprises phenotypically and prognostically heterogeneous disorders, which present a significant diagnostic challenge. The rapid and reliable identification of patients with MLN-TK may be delayed due to genetic complexity and significant phenotypic differences, including the chronic phase and primary/secondary blast phase (BP) of myeloid, lymphoid, or mixed phenotype in the bone marrow (BP-BM) and/or at extramedullary sites (extramedullary disease [EMD]). As a result, the entire armamentarium of conventional molecular genetic and cytogenetic techniques complemented by modern sequencing technologies, such as RNA sequencing or whole-genome sequencing, are often required to identify an underlying TK fusion. TK inhibitors (TKIs) with variable efficacy are available for all fusion genes, but a long-term favorable clinical course under TKI monotherapy is currently only observed in MLN-PDGFRA/PDGFRB fusion genes on imatinib. Because primary/secondary BP-BM/EMD occurs more frequently in MLN-FGFR1/JAK2/FLT3/ETV6::ABL1, a sequential combination of selective TKIs with or without prior intensive chemotherapy, rarely local radiotherapy, and/or subsequent allogeneic hematopoietic cell transplantation should be considered.

Chronic graft-versus-host disease (cGVHD) is associated with morbidity, mortality, impaired quality of life, prolonged immunosuppressive therapy, and infection risk after allogeneic hematopoietic cell transplantation (HCT). Major strides have occurred in the understanding of cGVHD biology; National Institutes of Health Consensus meetings have refined rigorous approaches to diagnosis, staging, and response criteria; major interventional trials have established standard benchmarks for treatment outcome; and 3 agents to date have been US Food and Drug Administration approved for treating corticosteroid-refractory cGVHD. Promising results from several recent trials have led some, but not others, to conclude that the risk of developing cGVHD is sufficiently low to be considered a major post-HCT complication of the past. We propose that it is time to critically examine the results of contemporary graft-versus-host disease (GVHD) prophylaxis regimens and discuss the state of the science and associated controversies in the spectrum of conclusions reached as to the risk of cGVHD. With these data, the current cGVHD incidence can be most precisely determined, and the present and future burden of cGVHD-affected patients can be accurately modeled. Through review of existing evidence, we highlight unresolved needs and opportunities to refine best GVHD prophylaxis or preemptive therapy approaches and optimize established cGVHD therapy, and make the argument that support of preclinical and clinical research is critical in improving patient outcomes.

Coagulation factor IX plays a central role in hemostasis through interaction with factor VIIIa to form a factor X-activating complex at the site of injury. The absence of factor IX activity results in the bleeding disorder hemophilia B. This absence of activity can arise either from a lack of circulating factor IX protein or mutations that decrease the activity of factor IX. This review focuses on analyzing the structure of factor IX with respect to molecular mechanisms that are at the basis of factor IX function. The proteolytic activation of factor IX to form activated factor IX(a) and subsequent structural rearrangements are insufficient to generate the fully active factor IXa. Multiple specific interactions between factor IXa, the cofactor VIIIa, and the physiological substrate factor X further alter the factor IXa structure to achieve the full enzymatic activity of factor IXa. Factor IXa also interacts with inhibitors, extravascular proteins, and cellular receptors that clear factor IX(a) from the circulation. Hemophilia B is treated by replacement of the missing factor IX by plasma-derived protein, a recombinant bioequivalent, or via gene therapy. An understanding of how the function of factor IX is tied to structure leads to modified forms of factor IX that have increased residence time in circulation, higher functional activity, protection from inhibition, and even activity in the absence of factor VIIIa. These modified forms of factor IX have the potential to significantly improve therapy for patients with hemophilia B.

Recent advancements in single-cell genomics have enriched our understanding of hematopoiesis, providing intricate details about hematopoietic stem cell biology, differentiation, and lineage commitment. Technological advancements have highlighted extensive heterogeneity of cell populations and continuity of differentiation routes. Nevertheless, intermediate "attractor" states signify structure in stem and progenitor populations that link state transition dynamics to fate potential. We discuss how innovative model systems quantify lineage bias and how stress accelerates differentiation, thereby reducing fate plasticity compared with native hematopoiesis. We conclude by offering our perspective on the current model of hematopoiesis and discuss how a more precise understanding can translate to strategies that extend healthy hematopoiesis and prevent disease.

von Willebrand factor (VWF) is a multimeric protein consisting of covalently linked monomers, which share an identical domain architecture. Although involved in processes such as inflammation, angiogenesis, and cancer metastasis, VWF is mostly known for its role in hemostasis, by acting as a chaperone protein for coagulation factor VIII (FVIII) and by contributing to the recruitment of platelets during thrombus formation. To serve its role in hemostasis, VWF needs to bind a variety of ligands, including FVIII, platelet-receptor glycoprotein Ib-α, VWF-cleaving protease ADAMTS13, subendothelial collagen, and integrin α-IIb/β-3. Importantly, interactions are differently regulated for each of these ligands. How are these binding events accomplished and coordinated? The basic structures of the domains that constitute the VWF protein are found in hundreds of other proteins of prokaryotic and eukaryotic organisms. However, the determination of the 3-dimensional structures of these domains within the VWF context and especially in complex with its ligands reveals that exclusive, VWF-specific structural adaptations have been incorporated in its domains. They provide an explanation of how VWF binds its ligands in a synchronized and timely fashion. In this review, we have focused on the domains that interact with the main ligands of VWF and discuss how elucidating the 3-dimensional structures of these domains has contributed to our understanding of how VWF function is controlled. We further detail how mutations in these domains that are associated with von Willebrand disease modulate the interaction between VWF and its ligands.

In September 2023, the US Food and Drug Administration approved momelotinib for the treatment of myelofibrosis (MF) with anemia, marking the fourth US regulatory approval of a Janus kinase inhibitor for MF. A positive opinion from the European Medicines Agency followed in November 2023. Momelotinib's ability to address splenomegaly, symptoms, and anemia, including in patients with thrombocytopenia (with platelet counts of ≥25 × 109/L), the ease of switching from ruxolitinib, and good tolerability uniquely position it to substantially impact the MF treatment landscape.