Histiocytic disorders are characterized by abnormal accumulation of myeloid-derived histiocytes and a shared biology marked by RAS/MAPK/ERK pathway activation, yet the rarity and heterogeneity of these conditions have limited the availability of robust, well-controlled clinical trials to guide therapy. This review highlights Langerhans cell histiocytosis, the most common subtype, and Rosai-Dorfman disease, a less common non–Langerhans cell histiocytosis entity, using them as key examples to illustrate how advancements in molecular diagnostics and targeted MAPK inhibitors are reshaping clinical management in histiocytic disorders. In both disorders, treatment approaches range from active observation in mild cases to more aggressive interventions in high-risk or progressive disease, emphasizing the spectrum of clinical presentations and the need for individualized, biology-driven strategies.
Low- and intermediate-risk myelodysplastic syndromes (LR-MDS and Int-MDS, respectively) are characterized by ineffective hematopoiesis, along with the presence of at least 10% dysplasia in one cell line, accompanied by a low number and depth of peripheral blood cytopenias, a low bone marrow blast percentage, and a score of ≤0 on the Molecular International Prognostic Scoring System (IPSS-M). The information gleaned from mutational profiles at the time of myelodysplastic syndrome (MDS) diagnosis and over subsequent time points help with classification and prognosis, guiding therapeutic decisions. In LR-MDS, these decisions are initially focused on improving symptom control and optimizing hematologic parameters. New therapeutic options to reduce the red blood cell (RBC) transfusion burden have emerged since 2020 and include luspatercept and imetelstat. Erythropoiesis-stimulating agents and lenalidomide also address anemia and are generally recommended to start at the time of transfusion dependency, although emerging data suggest that an earlier start of these interventions might offer clinical benefits. Patients can derive years of benefit from these approaches in LR-MDS, but despite these therapies, ultimately MDS will evolve into higher-risk MDS (HR-MDS)/acute myeloid leukemia. Even though most LR-MDS patients present with anemia, patients can have isolated thrombocytopenia for which thrombopoietin receptor analogues can be used if blasts are low. Immunosuppressive therapy such as antithymocyte globulin is favored in the hypocellular MDS setting. Dose-modified hypomethylating agent use can be considered for LR-MDS, although neither overall survival (OS) nor progression-free survival (PFS) has been shown to improve with this approach. Targeted therapy directed to the presence of an IDH1 mutation is U.S. Food and Drug Administration (FDA) approved for the rare IDH1 mutated MDS (<10% of the time) and consideration to use an IDH2 inhibitor for IDH2 mutated MDS (<5% of the time) is reasonable. Interestingly, IDH mutations seem to appear with increased frequency in older patients and in patients with underlying autoimmune/rheumatological disorders.1
Arterial and venous thromboses differ in pathophysiology but share overlapping risk factors such as obesity, metabolic syndrome, and aging. Patients with established arterial disease, such as coronary artery disease, stroke, and peripheral artery disease, may develop venous thromboembolism (VTE) during the acute or chronic phase of their illness. This creates therapeutic tension when anticoagulation for VTE overlaps with antiplatelet therapy. We propose a stepwise clinical approach that first identifies precipitating factors for VTE, then modifies antiplatelet therapy according to the chronicity of the arterial condition and finally estimates thrombosis against bleeding risk aided by scoring systems, available evidence for combination treatment, and interdisciplinary collaboration. Two clinical cases exemplify this stepwise approach.
While lenalidomide has been the established standard of care for maintenance after autologous stem cell transplantation in newly diagnosed multiple myeloma, risk-adapted maintenance strategies with the addition of proteasome inhibitors can provide additional benefit in high-risk disease. The widespread use of anti-CD38 monoclonal antibodies (mAbs) in induction and consolidation has further disrupted this paradigm, offering the use of anti-CD38 mAbs in maintenance. Novel immunotherapeutic approaches and minimal residual disease–guided maintenance strategies are being actively investigated. The evolution of maintenance strategies provides a window to a future where maintenance therapy is not only more effective at sustaining deep and durable responses but also more dynamic with careful de-escalation strategies.
Mediastinal gray zone lymphoma (MGZL) is defined in the international World Health Organization classification as a B-cell lymphoma with overlapping clinical, morphological, immunophenotypic, and molecular features between primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (CHL), particularly nodular sclerosis CHL (NSCHL). Recent molecular studies have highlighted the similarities between these 3 entities, relying on immune escape, JAK-STAT, and nuclear factor-κB pathway alterations without specific features related to MGZL. These studies shed light on the different pathobiology of extramediastinal cases, leading to the conclusion that these cases are generally better classified as diffuse large B-cell lymphoma (DLBCL)-not otherwise specified. The absence of Epstein-Barr virus (EBV) on the biopsy is also a desirable criterion, leading to the differential diagnosis of EBV-positive DLBCL. Most studies reporting clinical and treatment data suggest that more intensive induction regimens provide greater disease control compared to standard regimens. Given the paucity of dedicated clinical trials, it remains unknown if, and when, the evolving therapeutic options of PMBL and NSCHL will become available to those with MGZL, offering novel immune-based treatments to these patients with a higher risk of primary chemorefractory disease.
With the addition of antibody-based immunotherapy to frontline treatment regimens for B-lineage acute lymphoblastic leukemia (B-ALL), patients across the age spectrum now experience superior long-term survival. The pressing question for the field is whether immunotherapy may replace some of the intensive elements of the standard chemotherapy backbone to reduce overall toxicity and duration while maintaining superior outcomes. For young adults with B-ALL, most clinical trials have added immunotherapy to the intensive, pediatric-inspired regimens to achieve deeper remissions, while necessarily increasing duration, complexity, and possible toxicities. In contrast, clinical trials for older adults have used immunotherapy as a substitute to eliminate or reduce cytotoxic chemotherapy. And although survival outcomes for older adults remain distinctly inferior to those in the pediatric age group, it is hoped that the potential simplification of the chemoimmunotherapy backbone for all patients may be guided by the successes and shortcomings discovered in the treatment of older adults. In this article, I discuss the treatment of older adult patients with B-ALL in the immunotherapy era and how this approach may pave the way for implementing a deescalation strategy for younger adult patients with B-ALL, while maintaining the significant survival benefits that have been achieved during the past 20 years.
Allogeneic hematopoietic stem-cell transplantation is a curative modality for hematologic malignancies, bone marrow failure syndromes, hemoglobinopathies, and other nonmalignant disorders. Graft-versus-host disease (GVHD)—in its acute or chronic form—is an important transplant complication. The effective prevention of GVHD is crucial to the success of allotransplantation. Acute GVHD is mediated by the recognition of recipient antigens by donor T lymphocytes, with the subsequent activation and proliferation of T cells and establishment of an inflammatory cytokine cascade. Chronic GVHD is mediated by T-cell, B-cell, and macrophage activation with eventual inflammation and fibrosis. Standard approaches for GVHD prevention have been calcineurin-inhibitor (CNI) based, while newer approaches have focused on adding in-vivo T-cell modulation to a CNI backbone with antimetabolites such as posttransplant cyclophosphamide (PTCy), checkpoint blocking agents such as abatacept, or mammalian target of rapamycin (mTOR) inhibition with sirolimus. Still other approaches focus on blocking T-cell trafficking to target organs via integrin blockade (vedolizumab), cytokine blockade (JAK inhibitors), and B-cell blockade for chronic GVHD prevention. The use of PTCy and abatacept have improved allotransplantation safety and efficacy with human leukocyte antigen (HLA)-mismatched as well as HLA-matched donors, thus expanding the donor pool greatly for patients of all ancestries, and ushering in a new era in transplantation where donors are available for almost every patient.
Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy characterized by uncontrolled activation of the complement pathway, leading to microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. The advent of complement inhibitors such as eculizumab and ravulizumab has transformed aHUS management, markedly reducing morbidity and mortality. However, long-term therapy presents challenges, including infection risks, economic burden, and the need for indefinite treatment. Discontinuing complement inhibition is a pivotal clinical decision that requires careful risk assessment to prevent relapse. Pathogenic gene variants in complement- regulating proteins, particularly CFH, CFI, MCP/CD46, and C3, significantly increase the risk of relapse, particularly within the first 3 to 12 months after cessation. Patients with multiple pathogenic variants or variants of uncertain significance exhibit heightened vulnerability, necessitating extended monitoring. Clinical predictors such as young age, prior kidney transplantation, and the presence of extrarenal manifestations further stratify relapse risk. Additionally, dynamic biomarkers such as elevated soluble C5b-9 at the time of discontinuation may signal imminent relapse. Comprehensive postdiscontinuation surveillance, including laboratory assessment of kidney function, hemolysis markers, and complement activity, is crucial for early relapse detection. Emerging strategies for personalized risk assessment, including pharmacogenomic profiling and biomarker-guided monitoring, may optimize therapeutic decision-making in aHUS. This review synthesizes current evidence on the long-term management of aHUS, focusing on strategies for anticomplement therapy discontinuation, relapse prediction, and individualized monitoring.
After decades of research, gene therapy for hemophilia is now commercially available for both hemophilia A and B. Currently, two products, valoctocogene roxaparvovec (for hemophilia A) and etranacogene dezaparvovec (for hemophilia B), have been licensed following approval in the United States and several other countries. Therefore, clinicians must familiarize themselves with these novel treatment options just as they do with other newly available products in order to provide their patients the opportunity to consider which treatment may suit them best. Undoubtedly, gene therapy is a novel platform for treating human disease, and unlike other hemophilia treatments, its biology, mechanisms, and administration logistics are quite complex. Furthermore, additional products using different approaches have entered clinical trials, with more in the preclinical stages of development. This review's aims are (1) to deconstruct gene therapy in hemophilia and provide a basic framework for understanding its components and processes, including the transgene, the vector, and the delivery systems, in order to help clinicians present gene therapy as a treatment option in a shared decision-making model, better understand the clinical data, and explain gene therapy to their patients; (2) to gain knowledge of the currently approved gene therapies for hemophilia A and B, including their eligibility and exclusion criteria and the range of expected outcomes; and (3) to comprehend the shared decision-making process for these therapies and their implementation in clinical practice. In addition, a brief review of the currently approved products and those in clinical trials is presented, followed by a discussion of practical considerations for implementing gene therapy in practice.
Combined hypomethylating agent (HMA) plus venetoclax (Ven) therapy enables most older patients with acute myeloid leukemia (AML) to achieve clinical remission. Key objectives are now aimed at developing new triplet combinations to circumvent mechanisms of resistance and extend remission longevity and, by extension, survival. Genomically agnostic approaches combine hypomethylating agents and venetoclax (HMA-Ven) with novel agents directed at oncogenic pathways critical for leukemic cell survival, proliferation, metabolism, or differentiation. Challenges faced in the development of new HMA-Ven triplets include competition from targeted inhibitors, biological heterogeneity of AML, potential for additive toxicity, reduced efficacy from modifications to the HMA-Ven backbone, and the higher bar for success in older AML beyond the current standard of care.
POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome is a complex paraneoplastic syndrome related to a lambda-restricted low–tumor burden neoplasm. The diagnosis must be considered in the context of what might otherwise be believed to be a “monoclonal gammopathy of undetermined significance,” with unusual features including, but not limited to, peripheral neuropathy, thrombocytosis, and extracellular volume overload. Once a diagnosis of POEMS syndrome is made, besides very specific supportive care, the treatments resemble those of multiple myeloma or solitary plasmacytoma of the bone. Based on case series, autologous stem cell transplant is still a favored therapy with durable remissions even without maintenance therapy. Even before the era of therapeutic monoclonal antibodies, bispecific T-cell engagers, and chimeric antigen receptor antibodies, 10-year overall survival approached 80%. Patients achieving a complete hematologic response have a progression-free survival of 88% even without maintenance therapy. Herein, a case of a patient with a less-than-average outcome is described to highlight some of the long-term challenges and complexities of managing patients with POEMS syndrome.
Sickle cell disease (SCD), the most prevalent hemoglobinopathy globally, is a complex, systemic disorder with significant phenotypic variability and evolving clinical burden. As the therapeutic landscape expands—ranging from hydroxyurea and red blood cell transfusions to novel disease-modifying agents and curative approaches, such as hematopoietic stem cell transplantation and gene therapy—patient selection for each strategy becomes increasingly multifaceted. This article explores how clinical severity, genotype, age, organ involvement, access to care, and patient preferences interact in shaping therapeutic decisions. Two illustrative cases highlight how disease trajectory, individual choices, and real-world barriers influence eligibility and response to treatment. We propose a multidimensional framework for patient selection, incorporating both clinical indicators and patient-centered outcomes. While monotherapy with a single disease-modifying therapy remains the cornerstone of SCD treatment, all therapeutic decisions should be individualized. However, combination and curative approaches are more complex and require a comprehensive evaluation of efficacy, feasibility, and patient values. Emerging trends, including biomarker-driven stratification, inclusive clinical trials, and shared decision-making tools, coupled with the use of artificial intelligence, offer opportunities to better align therapy with the needs of diverse patients across settings. Ultimately, defining the “right” patient demands dynamic, context-sensitive evaluation, ensuring that therapeutic advances translate into equitable and valuable care for individuals with SCD globally.
Improved understanding of the molecular underpinnings of acute leukemia has led to advances in the detection of very low levels of leukemia-specific abnormalities, known as measurable residual disease (MRD). The limit of detection for modern next-generation sequencing and polymerase chain reaction–based assays is as low as 10–6, allowing for quantitative and longitudinal monitoring in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). In the period surrounding allogeneic hematopoietic cell transplantation (HCT), detectable MRD is clearly associated with poor outcomes, primarily due to an increased risk of morphologic relapse. In this review, we address the use of maintenance therapy for patients with acute leukemia, including those who are MRD-positive prior to and following HCT. Post-HCT azacitidine may have a role for MRD-positive AML. In AML with FLT3–internal tandem duplication mutation, post-HCT gilteritinib and sorafenib can be evidence-based strategies to target MRD. In ALL, blinatumomab is a powerful tool to eradicate MRD in patients with Philadelphia (Ph)-positive or Ph-negative ALL; tyrosine kinase inhibitors are indicated for post-HCT management of Ph+ ALL. Despite these advances, the optimal duration and type of intervention still remain unknown for many patients with acute leukemia who have peri-HCT MRD.
Allogeneic hematopoietic cell transplantation is a potentially curative therapy for patients with both malignant and nonmalignant disorders. To select the optimal donor for allogeneic hematopoietic cell transplantation, the first step is to search for a matched sibling donor or a matched unrelated donor, both of which yield comparable outcomes in the current clinical landscape. Additional donor options include haploidentical donors, mismatched unrelated donors, and umbilical cord blood donors. Newer transplant approaches have refined the use of these donor sources to improve outcomes. Beyond human leukocyte antigen compatibility, several non–human leukocyte antigen factors influence optimal donor selection. These include donor age, the presence of donor-specific antibodies, cytomegalovirus status, and ABO blood type compatibility. Various graft engineering strategies have been developed. These include posttransplant cyclophosphamide, T-cell depletion techniques such as CD34+ selection, CD45RA depletion, and αβ T-cell depletion, T regulatory purification, and umbilical cord blood expansion. Optimizing the cell dose used in transplantation is also critical to improving outcomes. All of these strategies combined allow nearly every patient to find a donor with continued improvements in outcomes.
Congenital thrombotic thrombocytopenic purpura (cTTP) arises from an inherited deficiency of ADAMTS13, causing a thrombotic microangiopathy with multisystemic sequelae. Acute cTTP relapse can cause arteriovascular thrombosis, and registry data suggest that later diagnosis and commencement of treatment are associated with increased morbidity. Undiagnosed or “nonovert” cTTP may also be associated with end-organ damage. Treatment is based on ADAMTS13 replacement, previously limited to plasma and factor VIII concentrates and now expanded to recombinant ADAMTS13, which can achieve higher peak and trough levels with smaller volumes. Now that treatment options are improved, we need to focus on prophylaxis and the clinical impact of this lifelong condition. Beyond treatment of acute TTP relapses, symptoms such as headaches, abdominal pain, and lethargy without overt laboratory relapse may reflect subacute TTP and herald later end-organ damage. We need further longitudinal data on how to optimize care. Key questions remain about prophylaxis and how to target optimal control of this condition through the alliance of improved treatment delivery and measures of clinical outcome.
The introduction of CAR (chimeric antigen receptor) T-cell therapy and bispecific antibodies into clinical practice has revolutionized the treatment landscape of relapsed/refractory multiple myeloma (RRMM). Both modalities have shown impressive clinical efficacy with slightly different but overall manageable toxicity profiles. At present, two B-cell maturation antigen (BCMA)-targeted CAR T-cell therapies, idecabtagene vicleucel and ciltacabtagene autoleucel, are approved for standard use in the United States. There are currently 4 commercially approved bispecific antibodies: teclistamab, elranatamab, and linvoseltamab, which target BCMA, as well as talquetamab, which targets the GPRC5D antigen on the surface of plasma cells. In this review, we explore (a) the advantages and challenges of integrating CAR T-cell therapy earlier in the RRMM treatment course; (b) the safety and efficacy of bispecific antibodies and their evolving role in the current RRMM treatment paradigm; (c) practical considerations for both modalities, focusing on patient selection and supportive care strategies; and (d) recommendations for sequencing of T-cell redirecting therapies to maximize long-term outcomes.
JAK2 unmutated/wild-type erythrocytosis is a prevalent condition encompassing a wide spectrum of hereditary and acquired entities. It is conventionally defined by the same hemoglobin/hematocrit thresholds as for polycythemia vera. Incidence has been reported to be between 0.13% and 4.1%. The most clinically relevant step in the workup of erythrocytosis is the exclusion of polycythemia vera through JAK2 mutation screening. Consideration of relative polycythemia, normal outliers, and the influence of erythropoietic drugs and comorbidities is also imperative. Distinguishing long-standing from newly acquired erythrocytosis further streamlines the diagnostic process. Hereditary erythrocytosis (HE) is lifelong and typically associated with a positive family history. Subnormal serum erythropoietin (EPO) suggests an EPO receptor mutation. Otherwise, oxygen tension at 50% hemoglobin saturation (p50) discerns between high oxygen-affinity hemoglobin variants, 3-bisphosphoglycerate deficiency, methemoglobinemia, and PIEZO1 mutations (low p50) and germline oxygen-sensing pathway/other rare mutations (normal p50). Acquired erythrocytosis results from hypoxia-driven factors (eg, cardiopulmonary, altitude, renal artery stenosis) and other mechanisms of EPO overproduction (eg, EPO-secreting tumors) or hypersensitivity, as well as EPO-independent mechanisms. Drugs (eg, sodium glucose co-transporter-2 inhibitors, testosterone) are also common causes. Idiopathic erythrocytosis is a diagnosis of exclusion, increasingly attributed to underlying genetic mutations/polymorphisms. There are currently no evidence-based treatment guidelines. Low-dose aspirin and/or phlebotomy (with frequency determined by symptom relief) might be considered on an individualized basis in the presence of hyperviscosity symptoms, cardiovascular comorbidities, and/or a history of thrombosis. Aggressive control of cardiovascular risk factors is recommended in all. A graphic abstract representation is provided in Figure 1.
Adoptive T-cell therapy has emerged as a transformative modality in cancer immunotherapy, building upon foundational principles established in allogeneic hematopoietic stem cell transplantation. In this setting, while donor T cells mediate curative graft-versus-leukemia and graft-versus-infection effects, their alloreactivity poses significant risks. Gene transfer strategies—such as suicide gene insertion—have enabled the safer use of donor lymphocytes by allowing the selective elimination of T cells in case of adverse events. With this initial gene therapy approach, several lessons on the function, persistence, safety, and efficacy of engineered T cells were learned. More recently, advances in genome editing technologies have enabled precise manipulation of T-cell genomes and function, including disruption of endogenous T-cell receptors (TCRs) and insertion of tumor-specific receptors, such as chimeric antigen receptors and tumor-specific TCRs. Integration of T-cell manufacturing protocols optimized for persistence and resistance to immune suppression—largely facilitated by the possibility to simultaneously edit multiple genes (multiplex genome editing) in the same cells—has positioned engineered T cells as programmable and persistent therapeutics. Here, we briefly review key milestones, challenges, and innovations in T-cell gene engineering, from allogeneic hematopoietic stem cell transplantation to next-generation TCR-edited immunotherapies.
Hemophagocytic lymphohistiocytosis (HLH) and the related HLH-spectrum disorders macrophage activation syndrome, macrophage activation-like syndrome, and treatment-associated immune-effector-cell–associated HLH-like syndrome are extreme forms of too much inflammation (TMI). Adult patients with HLH associated with hematologic malignancies have a 70% to 80% mortality rate due to delayed diagnosis, prolonged immunosuppression with associated secondary infections, and disease recurrence. In recent years, educational efforts and epidemiological evolution have increased diagnostic awareness. This has been catalyzed by the COVID-19 pandemic, the first approved anti-interferon gamma antibody for primary relapsed/refractory HLH, advancements in the treatment of posttransplant graft-versus-host disease, and the broad availability of T-cell–engaging therapeutics. These truly challenging-to-diagnose entities under the cytokine storm umbrella confer TMI, causing multiorgan dysfunction and early death. Novel prognostic models, differential diagnosis with the help of advanced diagnostic algorithms, preemptive therapeutic interventions, and more individualized cytokine-directed treatment options have moved this previously neglected area in adult hematology to the forefront of the hematologist's daily practice.
Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by decreased platelet counts and a variable propensity for bleeding. Significant strides have delineated the pathophysiologic mechanisms of ITP and led to new therapeutics. Despite these advances, 5% to 30% of patients persist with low platelet counts and/or ongoing bleeding. This review summarizes the current definitions and pathophysiology of refractory ITP, revisiting diagnostic realms and management strategies for these difficult-to-treat patients.
