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

Despite the enormous progress made in the treatment of multiple myeloma (MM) with various treatment choices in frontline and relapse settings, treatment of high-risk (HR)MM remains a therapeutic challenge. Definition of HR disease is dynamic and mainly based on cytogenetic assessment showing typical cytogenetic abnormalities. Most recently, the International Myeloma Society and the International Myeloma Working Group published a revision of HR criteria, IMS-IMWG Consensus Genomic Staging. Immediate identification of HRMM at primary diagnosis is crucial to refer the patients to optimal treatment. Emerging data, especially from clinical trials designed explicitly for HR patients, demonstrated that upfront quadruplet treatment followed by consolidation and continuous combination maintenance, including high dose melphalan and autologous stem cell transplantation for patients who qualify, is the current best approach leading to a markedly improved prognosis. The primary treatment goal is the rapid achievement of sustained minimal residual disease- negative response with treatment continuation beyond to avoid early relapses and evolvement of resistant clones. A distinct subgroup of patients, the so-called functional HR patients, are defined as relapsing between 12 and 18 months despite optimal frontline treatment. The unmet need for effective treatment options in this challenging situation is now partially mitigated by the introduction of B-cell maturation antigen-directed T-cell-engaging immunotherapies. Early data show favorable outcomes, with treatments with chimeric antigen receptor T-cells achieving durable responses.

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.

Although the management of β-thalassemia has improved significantly, patients still suffer from many complications, including thrombotic events. A hypercoagulable state has been demonstrated in these conditions, particularly in non-transfusion-dependent β-thalassemia, because of disease-specific contributors that play a role in the pathogenesis, including reactive oxygen species, pathological erythroid cells, circulating microparticles, free heme, and endothelial activation. Splenectomy further contributes to the complexity of thrombotic risk in such patients, together with emerging complications related to increased survival, such as atrial fibrillation. Moreover, in recent years the role of new drugs in further modifying the thrombotic risk of these patients has been demonstrated, as in the case of luspatercept. However, its role still needs to be elucidated. The currently available prevention and clinical management of thrombosis in thalassemia patients mainly relies on the international guidelines for the general population, although, given the peculiar pathophysiology and the disease-related risk factors, robust data and evidence are necessary to develop dedicated guidelines.

Atherosclerotic cardiovascular disease (ASCVD) encompasses a spectrum of vascular conditions, including coronary artery disease (CAD) and lower extremity peripheral artery disease (PAD), which frequently coexist. In the setting of ASCVD, there is a common underlying pathophysiology for acute ischemic events related to platelet activation and thrombin generation. The scope of this review focuses on the role of dual-pathway inhibition, the approach combining antiplatelet and antithrombotic therapy, for improvement in cardiovascular outcomes in patients with ASCVD. To determine which patients with CAD and PAD may benefit from dual-pathway inhibition, a brief overview of clinical presentations for both stable CAD and the spectrum of lower extremity PAD is outlined.

Monoclonal gammopathy is observed in approximately 10% of patients with peripheral neuropathy, which is particularly common in those with the immunoglobulin M monoclonal component. The diagnostic challenge lies in determining whether the neuropathy is causally related to the paraprotein or merely coincidental. Physicians must be familiar with the spectrum of monoclonal gammopathy-associated neuropathies, including anti-myelin-associated glycoprotein neuropathy, amyloid light chain amyloidosis, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies), and cryoglobulinemia, as well as their clinical, electrophysiologic, and immunologic characteristics. Initial workup includes serum protein electrophoresis, immunofixation, free light chain analysis, and targeted antibody testing based on the paraprotein and neuropathy phenotype. Close collaboration between neurologists and hematologist-oncologists is essential for accurate diagnosis and appropriate treatment, which may involve both immunotherapy and targeted therapies for the underlying hematologic disorder.

Pregnancy is high risk for individuals with sickle cell disease (SCD), and maternal morbidity and mortality are unchanged in middle- and high-income settings. As many as 30% of SCD pregnancies may be uncomplicated, but most are associated with complications. The odds of severe maternal morbidity are much higher in Black women with SCD than in Black women without SCD or non-Black women. Prophylactic red cell transfusions are considered low risk according to American Society of Hematology guidelines and are the only disease-modifying therapy available for use in pregnancy. When initiated in the preconception and/or prenatal period, treatment is associated with reduced maternal and fetal mortality, painful crises, and pulmonary complications in pregnancy. Furthermore, pain occurs in as many as 75% of SCD pregnancies; in meta-analyses and randomized controlled data, transfusions reduce pain events during SCD pregnancy. British, American, and French guidelines make recommendations regarding transfusion indications in SCD pregnancy. Many people with SCD, and most with hemoglobin SS or hemoglobin Sβ0-thalassemia, have an indication for prophylactic transfusion during pregnancy. Transfusion may meaningfully improve outcomes for pregnant people with SCD. We discuss our approach to managing SCD pregnancy using the case of a patient cared for in the mid-Atlantic region of the United States.

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.

Anti-CD19 chimeric antigen receptor (CAR) T cells can induce complete remission in the majority of children and young adults affected by multiple relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL) and provide potential long-term cure through continuous surveillance against leukemic recurrence. The presence of B-cell aplasia represents an indirect marker of CAR T functional persistence. Patients treated with tisagenlecleucel who present with early (within 6 months from infusion) B-cell recovery (BCR) have an increased risk of relapse and merit further treatment. In this work, we describe a pediatric clinical scenario and discuss the possible interventions-that is, hematopoietic stem cell transplantation (HSCT), second CAR T infusion, and maintenance chemotherapy-for similar patients with early BCR after CAR T, based on the available literature. We advocate for HSCT with total body irradiation (TBI) in children who had never received transplantation and can safely undergo TBI, while those who already had a first HSCT with TBI or present with a contraindication to TBI, in the absence of available clinical trials, can be considered for maintenance chemotherapy, given early indications of good tolerability and promising noninferior outcomes. Patients with Philadelphia-positive ALL should receive tyrosine kinase inhibitors in the context of either HSCT or maintenance chemotherapy. For young adults, 3 different commercial CAR T are available, but so far, clinical data are insufficient to support any specific consolidation strategy.

Quadruplet induction regimens containing anti-CD38 monoclonal antibodies in combination with a triplet backbone are providing deeper and more durable responses in newly diagnosed multiple myeloma (NDMM) patients, and at the same time, questioning the role of autologous stem cell transplant as part of consolidation, especially in certain subgroups. While several studies are evaluating the rate of sustained minimal residual disease (MRD) achieved when combining quadruplet regimens to transplant, other studies are focusing on the relevance of pursuing transplant in those who achieved MRD with induction. Current evidence supports autologous stem cell transplant as a key consolidation strategy while ongoing studies refine risk-adapted and MRD-guided approaches. We have yet to see how new immunotherapies that are moving to front-line therapy will challenge the role of transplant in the future.

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.