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

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.

Complement-mediated thrombotic microangiopathy (C-TMA), also referred to as atypical hemolytic uremic syndrome (aHUS), is a rare but severe cause of microangiopathic hemolysis and organ injury. Despite advances in understanding its pathophysiology and new nomenclature distinguishing C-TMA (aHUS) from other TMAs, diagnosis remains difficult because there is no single definitive diagnostic test. This update focuses on emerging data for functional complement assays (eg, modified Ham assay and human microvascular endothelial cell (HMEC-1) C5b-9 deposition assays) as adjunctive tests that may directly demonstrate complement hyperactivity in suspected C-TMA. A systematic diagnostic algorithm incorporating rapid exclusion of thrombotic thrombocytopenic purpura and Shiga toxin-producing Escherichia coli-HUS, careful evaluation of secondary causes, and integration of genetic and functional testing may improve diagnostic accuracy and guide the prompt use of targeted complement inhibitors.

In the last decades, we have witnessed huge progress in the understanding of iron metabolism and the consequences of its dysregulation in case of overload, and we have understood how, in the case of hematopoietic transplantation, the toxicity of iron and the related damage acquired over the years is important in addition to the overload itself. This article summarizes and discusses, in real-world practical examples, what knowledge has been acquired, how much can be translated into clinical practice today, and how much is best explored only in a well-defined and controlled experimental environment.

Autoimmune hemolytic anemia (AIHA) is caused by premature erythrocyte destruction mediated by autoantibodies (auto-Ab) with or without complement activation. The most frequent form (60%-70% of cases) is warm AIHA (wAIHA), driven by immunoglobulin G auto-Ab that react at body temperature. Cold agglutinin disease (CAD, 20%-25%) is the second most common form and is caused by immunoglobulin M auto-Ab that usually react at temperatures <20°C and strongly activate complement. Rarer forms (5%-10%) include mixed AIHAs (wAIHA plus CAD), and paroxysmal cold hemoglobinuria. Here, we present the management of wAIHA, as CAD is discussed separately. Approximately 50% of wAIHA are primary, whereas the remainder are secondary to various conditions (infections, lymphoproliferative disorders, systemic or organ-specific autoimmune diseases, congenital immunodeficiencies, hematopoietic stem-cell transplantation, and several drugs, including immune checkpoint inhibitors). The disease is highly heterogeneous, ranging from fully compensated to life-threatening, and frequently has a relapsing course. Standard first-line therapy includes steroids with or without intravenous immunoglobulin, transfusions when anemia is clinically significant, prophylactic anticoagulation for severe hemolysis, and recombinant erythropoietin when reticulocytopenia/inadequate bone marrow compensation is present. For severe cases, high-dose steroids and plasma-exchange may be considered. Rituximab is now the preferred second-line option for relapsed/refractory patients, comparing favorably with the traditional splenectomy. The latter is increasingly reserved for later lines together with classic immunosuppressants. Several novel treatments are in development for refractory wAIHA, encompassing drugs targeting B-cells (parsaclisib, ibrutinib, rilzabrutinib, zanubrutinib, obexelimab, ianalumab, povetacicept), plasma cells (bortezomib, daratumumab), spleen tyrosine kinase (fostamatinib, sovleplenib), and the neonatal Fc receptor (nipocalimab).

Conditioning regimens play an essential role in allogeneic transplantation by facilitating engraftment and eradicating malignancies. The landscape of conditioning regimens has undergone an evolution in the concept of intensity. Novel conditioning strategies aim to provide highly efficacious regimens with improved toxicity profiles. Integrating disease- specific chemotherapy and targeted agents into conditioning regimens provides enhanced disease elimination and relapse prevention. Agents like treosulfan provide safer conditioning with a favorable toxicity profile for patients with older age or medical comorbidities and can lower the incidence of long-term complications for younger patients. Additionally, methodologies for precise and targeted radiation delivery with minimal off-target effects are emerging. A promising development is radioimmunotherapy-based regimens that preferentially deplete hematopoietic cells and spare nonhematopoietic tissues. These advancements necessitate reexamination and harmonization of conditioning intensity stratification schemes for a more personalized and selective approach.

Venous thromboembolism (VTE) is a frequent complication in patients with cancer, especially those receiving systemic therapy in the ambulatory setting. Despite being a largely preventable condition, it remains a leading cause of morbidity and mortality in this patient population. Risk prediction models, such as the Khorana score, have been developed to stratify patients according to their underlying risk of VTE and identify those most likely to benefit from thromboprophylaxis by improving its risk-benefit ratio. Recent evidence supports the efficacy and safety of both low molecular weight heparin and direct oral anticoagulants in reducing VTE incidence in ambulatory patients with cancer who are receiving systemic therapy and are at high risk of VTE. Nevertheless, despite guideline recommendations warranting a risk-based approach, studies persistently show low adoption of thromboprophylaxis in this patient population. Barriers to implementation are complex, including clinician-, patient- and system-related factors. However, promising implementation strategies, including electronic health record integrated risk calculators, structured education programs, and patient-centered care pathways, have shown potential in improving adherence to guidelines and better clinical outcomes. This review summarizes the current evidence for thromboprophylaxis in patients with cancer, explores the challenges in translating evidence into practice, and highlights successful models designed to close the gap between guidelines and clinical practice.

Contemporary chemotherapy protocols have improved cure rates for children, adolescents, and young adults (CAYA) with T-lineage acute lymphoblastic leukemia (T-ALL) to greater than 80%. Unfortunately, outcomes for CAYA with relapsed and refractory disease, as well as older adults, remain poor. A key goal in the treatment of T-ALL therapy is preventing relapse; however, it is challenging to identify high-risk patients. Recently, several genomic initiatives have identified distinct biological subtypes of T-ALL and have correlated disease biology, including mutational status, transcriptional phenotype, and clonal drivers, with therapy response and outcome. The integration of genomic profiling into clinical diagnosis and treatment has promise to guide risk stratification, targeted therapy, and clinical trial design for high-risk patients. This review highlights the recently mapped genomic landscape of T-ALL, with particular emphasis on recently identified genomic molecular signatures, their utility in risk stratification, and targeted therapy selection for refractory cases.

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.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of B-cell malignancies, but similar success in T-cell and myeloid leukemias has remained elusive due to unique biological and logistical barriers. T-cell acute lymphoblastic leukemia poses challenges such as fratricide, product contamination, and profound immunosuppression from T-cell aplasia. Gene editing, protein expression blockers, and antigen selection strategies have been employed to mitigate these risks, while allogeneic CAR T-cell platforms offer rapid deployment but carry risks of graft-versus-host disease and immune rejection. Early-phase trials targeting CD5 and CD7 have demonstrated promising response rates, particularly with gene-edited or bicistronic constructs, although toxicities and the need for consolidative hematopoietic stem cell transplantation remain significant hurdles. Similarly, CAR T-cell therapy for acute myeloid leukemia faces the dual obstacles of antigen nonspecificity and a highly immunosuppressive tumor microenvironment. Multiantigen targeting, logic-gated designs, and epitope editing have emerged to improve specificity and safety. Novel approaches to overcome the immunosuppressive milieu include checkpoint blockade and cytokine pathway modulation. Allogeneic and "off-the-shelf" CAR T-cell products are being developed to address manufacturing challenges in patients with rapidly progressive disease. Collectively, these advances highlight the potential of cellular therapies in high-risk leukemias and underscore the importance of continued innovation to improve outcomes in these historically treatment-refractory populations. Using a real-world case, we highlight the major challenges and innovative strategies shaping CAR T-cell therapy for T-cell acute lymphoblastic leukemia and acute myeloid leukemia.

Follicular lymphoma is the most common indolent lymphoma, with a favorable prognosis and survival measured in decades. However, approximately 15% to 20% of patients encounter early disease progression, termed POD24, within 24 months from diagnosis or treatment initiation. Recognizing the correlation between POD24 and a heightened risk of lymphoma-related death has sparked intensive investigations into the clinical and biological determinants of POD24 and the development of innovative treatment strategies targeting this group. Research is also ongoing to understand the varying impact of POD24 based on different clinical contexts and the implications of early histologic transformation on POD24 prognosis. Recent investigations have uncovered potential new predictors of POD24, including genetic and nongenetic alterations as well as some conflicting F-fludeoxyglucose-positron emission tomography characteristics such as maximum standardized uptake value and total metabolic tumor volume. These developments, together with clinical predictors, have led to the emergence of several clinicopathologic tools to help identify at diagnosis patients who may be at higher risk for POD24. As these models are not routinely used, more work is needed to develop new risk-stratification strategies integrating clinical and molecular risk profiling that can be easily implemented in clinical practice to drive therapeutic choice. This review aims to delineate the modest but incremental progress achieved in our understanding of POD24, both clinically and biologically. Furthermore, we offer insights into the best practices to approach POD24 in the current era, aspiring to chart a new path forward to optimize patient outcomes.