Hematology. American Society of Hematology. Education Program最新文献

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.

In the past 20 years, advances in genomic technologies have greatly improved our understanding of pediatric acute myeloid leukemia (AML). Today, cytogenetic tests can detect structural changes in approximately 75% of cases and remain a main tool for assessing risk. Recent technologies, such as next-generation sequencing, are revealing additional structural alterations (cryptic fusions) and mutations that often cooperate to influence disease biology and treatment response. This evolving genetic landscape has identified unique childhood subtypes of AML defined by specific fusions, such as NUP98::NSD1, CBFA2T3::GLIS2, and varied KMT2A rearrangements, which are linked to distinct clinical outcomes. Emerging data also point to the poor prognosis associated with certain subtypes of NPM1, like the NPM1-D isoform. Additionally, mutations in genes like WT1, DNMT3A, and TP53, the latter of which are rare in childhood AML, may influence patients' outcomes, particularly when occurring in combination. Targeted therapies, including FLT3, BCL2, and menin inhibitors, are beginning to reshape treatment, offering more personalized approaches. However, integrating these drugs effectively into the patient's treatment strategy remains challenging due to the genetic complexity and rarity of pediatric AML. Key issues ahead include identifying which genetic features truly affect outcomes, using this information to personalize therapy, predicting who will benefit from targeted drugs, and choosing the best markers to track disease response over time. Looking forward, collaborative efforts are urgently needed to validate pediatric-specific biomarkers, test novel drug combinations, and link genetic data to clinical outcomes to design trials and future treatment strategies.

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.

Bleeding disorder of unknown cause (BDUC) is increasingly recognized as a common diagnosis among adult patients with mild to moderate bleeding symptoms and is reflective of unremarkable hemostatic tests despite a clinically relevant bleeding tendency. While extensive clinical and basic research has been conducted on the bleeding phenotype and underlying mechanisms of BDUC, great uncertainty remains regarding the long-term risk for spontaneous bleeding and the bleeding risk after hemostatic challenges. Currently available data suggest that a substantial portion of BDUC patients continue to experience spontaneous bleeding symptoms, such as easy bruising, epistaxis, and heavy menstrual bleeding. Risk factors associated with the persistence of these symptoms include the presence of the respective symptom prior to the BDUC diagnosis and a higher baseline bleeding score. Furthermore, a large proportion of BDUC patients report bleeding complications after surgery or child delivery prior to initial investigations. Patients with prior bleeding complications after such events, patients with blood group O, and patients who did not receive hemostatic prophylaxis demonstrate an increased risk for postinterventional bleeding during follow-up. Although BDUC remains a diagnosis of exclusion, accumulating data underscore the need to recognize it as a potentially persistent clinically relevant condition. Future studies should focus on refining diagnostic algorithms, investigating underlying mechanisms, and developing predictive tools for bleeding risk to improve individualized management strategies.

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.

The clinical benefits of iron overload (IOL) management in hereditary anemias, including organ preservation and dramatically improved overall survival (OS), are widely accepted. Adult myelodysplastic syndrome (MDS) patients are older and may have comorbidities, treatments to extend OS are limited, and the clinical benefits of IOL management have been more challenging to demonstrate due to little prospective data in this population. However, current prognostic systems identify MDS patients with reasonable life expectancy who may benefit from IOL management. Half of MDS patients ultimately become dependent on red blood cell transfusion and develop transfusional IOL. Considerable preclinical and clinical data have accumulated indicating the adverse impact of IOL on multiple cellular and clinical end points and a clinical benefit to IOL management in MDS, which should be considered in some patients. Here we provide an overview of salient data in the usual (nonhematopoietic stem cell transplant) clinical MDS setting, summarize mechanisms of iron toxicity including increased radiologically detectable organ stores and redox-active iron-mediated tissue damage, furnish strategies for the identification of IOL, and suggest a framework for IOL severity and IOL reduction. We review which patients are appropriate for IOL management, recommend an appropriate time to intervene, discuss evidence supporting a clinical benefit to IOL management, and recommend how to off-load iron. We identify data gaps for future study and forecast future tools that may become available to minimize IOL toxicity in MDS.

Combination therapies in acute myeloid leukemia (AML) are an area of current investigation due to the potential of overcoming resistance by targeting multiple pathways simultaneously. Triplet therapies combining hypomethylating agents, venetoclax, and targeted inhibitors are emerging as a promising therapy for older patients with AML unfit for intensive chemotherapy. These regimens have predominantly been studied in FLT3- and IDH1/2-mutated AML with attainment of high rates of measurable residual disease-negative composite remissions. Notably, patients with FLT3-internal tandem duplication and IDH1-mutated AML appear to garner a significant benefit from combination treatment due to poor duration of response to hypomethylating agents/venetoclax alone. While effective, the need to remain on indefinite therapy for individuals who are not stem cell transplant candidates and dose optimization/de-escalation strategies remain critical concerns. Herein, we aim to review the current treatment landscape of newly diagnosed and relapsed/refractory FLT3- and IDH1/2-mutated AML and the role of triplet regimens in these molecular subgroups.

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.

Sickle cell disease (SCD) is an acquired hypercoagulable state defined by the presence of prothrombotic alterations of the coagulation system, increased platelet activation, and endothelial disruption. These changes are associated with increased incidence of venous thromboembolism (VTE). There is interest in investigating the role of primary thromboprophylaxis, especially with the use of central venous catheters, perioperatively and during the last trimester of pregnancy and postpartum. Like the general population of patients with VTE, direct oral anti-Xa antagonists are being widely used as anticoagulation for secondary prophylaxis.

Before effective iron chelation became available, patients with transfusion-dependent thalassemia often died from iron-induced cardiomyopathy and endocrine failure in their second decade of life. This experience shaped long-standing expectations of poor outcomes and continues to fuel provider and patient anxiety in all conditions associated with iron overload. While severe iron overload and toxicity still cause considerable morbidity and mortality globally, advances in the understanding of iron metabolism, noninvasive organ-specific iron monitoring, and chelation therapy have significantly reduced their impact. Clinical insights from hemoglobinopathies have reinforced iron biology findings from animal models and highlighted shared mechanisms of iron toxicity across disorders, guiding broader management approaches that address the prevention of iron toxicity independently of the removal of organ iron burden. The resulting significant improvement in survival now presents new challenges tied to prolonged exposure to both anemia and iron overload, which must be addressed in long-term treatment planning.