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

The options for frontline chronic lymphocytic leukemia (CLL) treatment continue to expand. Therapies include monotherapy with a Bruton's tyrosine kinase inhibitor (BTKi), doublet therapies such as venetoclax with intravenous obinutuzmab or an oral BTKi, and triplet therapy combining BTKi, venetoclax, and CD20 antibody. Treatment duration also is increasingly variable, from fixed duration to utilization of undetectable minimal residual disease (uMRD) to determine optimal treatment completion. Currently, the best option for an individual patient requires a multifaceted approach considering the individual's cytogenetics, comorbidities, and personal preferences, including time-limited therapy vs continuous treatment. In this article, we outline the current state of frontline CLL including ongoing questions and future directions.

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.

Diagnostic and treatment advances have revolutionized the landscape of immune-mediated thrombotic thrombocytopenic purpura (iTTP). With the widespread availability of ADAMTS13 testing and novel therapies, outcomes based primarily on platelet counts are no longer sufficient. Clinical definitions have recently been updated to reflect this progress. Given the efficacy of preemptive rituximab in preventing clinical relapses, experts now recommend every 3-month monitoring of ADAMTS13 in remission. With improved survival, long-term sequelae-including obesity, cardiovascular disease, chronic kidney disease, neuropsychiatric impairment, obstetric complications, and reduced life expectancy-are increasingly being recognized. This review explores the evolving landscape of long-term management in immune-mediated thrombotic thrombocytopenic purpura, highlighting current challenges in surveillance, immune suppression in the second line (and beyond), and emerging opportunities for recognition of long-term sequelae.

Relapse remains the leading cause of failure after allogeneic stem cell transplantation (allo-SCT) for hematologic malignancies. Donor lymphocyte infusion (DLI), the infusion of lymphocytes from the original stem cell donor, was introduced in the late 1980s as a strategy to prevent or treat relapse by augmenting the graft-versus-leukemia (GvL) effect. Over time, DLI has been used in various settings: initially as therapeutic DLI for overt relapse and later as preemptive DLI, administered in response to early signs of relapse, such as persistent or recurrent measurable residual disease (MRD), or as prophylactic DLI to mitigate high relapse risk before clinical relapse occurs (see Visual Abstract). However, questions remain regarding how, when, and in whom DLI is best deployed, reflecting ongoing controversy and heterogeneity in clinical practice. A recent survey of 165 European Society for Blood and Marrow Transplantation centers across 43 countries reported that DLI was used prophylactically for high-risk hematologic diseases in 43.8% of these centers. DLI was used preemptively for MRD positivity in 86.9% of centers and for mixed chimerism in 73.1%. Therapeutic DLI was administered for hematologic relapse in 73.1% of centers. Active graft-versus-host disease and active infections were considered absolute contraindications by 85.6% and 57.5% of the centers, respectively. This observed variability in center practices underscores the need to clarify the "who, when, and why" of posttransplant cellular interventions. In this review, we explore DLI strategies and the potential sequencing with novel targeted therapies across prophylactic, preemptive, and therapeutic applications, illustrated through case examples in patients with acute myeloid leukemia. We highlight findings from retrospective, as well as the scarce prospective studies and extend considerations to other indications, including chronic myeloid leukemia, myelofibrosis, and acute lymphoblastic leukemia. Additionally, we review emerging combination strategies with targeted therapies across different hematologic malignancies and adoptive cell therapies beyond conventional DLI.

Pharmacologic targeting of the menin-KMT2A protein-protein interaction has emerged as a therapeutic breakthrough for acute leukemias harboring KMT2A rearrangements or NPM1 mutations. The first-in-class menin inhibitor (revumenib) achieved accelerated regulatory approval in November 2024 for monotherapy of relapsed/refractory KMT2A rearranged leukemia. Next-generation agents (ziftomenib, bleximenib, enzomenib, BMF-219) have displayed similar composite complete remission rates (20-35%) and overall response rates (45-65%) in heavily pretreated KMT2Ar and NPM1m acute myeloid leukemia (AML) with measurable residual disease (MRD) negativity and prolonged overall survival (5-7 months). While all menin inhibitors result in on-target blast differentiation with clinical sequelae ("differentiation syndrome") in 10% to 20% of patients, not all menin inhibitors are the same, with differing safety, toxicity (heartrate corrected QT interval (QTc) prolongation, cytopenias), and pharmacokinetic profiles. Acquired mutations in the menin gene described in 39% of post-revumenib relapses have not been identified following other inhibitors (ziftomenib, bleximenib), prompting new questions about resistance mechanisms. These promising results swiftly led to the launch of multiple trials of menin inhibitors combined with intensive (cytarabine and anthracycline) and nonintensive (venetoclax and hypomethylating) chemotherapy backbones. To date, these triplets have yielded high response rates (ie, ≥80% in de novo, 50-70% in relapsed) with most patients achieving MRD negativity and prolonged one-year survival. Ongoing/pending phase 3 trials will clarify whether menin blockade should be incorporated into frontline and maintenance regimens for all patients with KMT2A rearranged or NPM1 mutant disease. In the current era, menin inhibition remains a key pillar of the success of precision medicine for AML therapy.

Sickle cell disease (SCD) is a genetically and clinically heterogeneous disorder marked by hemolysis and vaso-occlusion, leading to a wide range of acute and chronic complications. While newborn screening enables early identification, the optimal timing for initiating disease-modifying therapies (DMTs) remains a critical and evolving question. This review explores how genetic and clinical risk factors, along with phenotypic variability, influence treatment timing, emphasizing a shift toward earlier and more personalized interventions. Hydroxyurea, the most widely used DMT, demonstrates strong evidence for early initiation in severe genotypes yet is underutilized due to concerns around long-term effects and adherence challenges. Additional therapies, such as L-glutamine, crizanlizumab, and formerly voxelotor, highlight the growing yet complex therapeutic landscape. Curative and transformative options, such as hematopoietic stem cell transplantation and newly approved gene therapies, underscore the need for individualized decision-making based on risk, disease trajectory, and patient goals. Rethinking treatment paradigms to incorporate multiagent approaches, biomarker-driven strategies, and earlier intervention may yield improved outcomes. Ultimately, optimizing the timing of therapy initiation requires moving from reactive to proactive care models that consider risk, clinical severity, and evolving therapeutic options, with the goal of improving quality of life and long-term survival for individuals living with SCD.

Monoclonal gammopathy of renal significance (MGRS) represents a clinical entity where clonal plasma or B-cell proliferative disorders secrete a monoclonal protein that leads to renal damage without meeting the diagnostic criteria for overt hematologic malignancies such as multiple myeloma or lymphoma. The diagnosis typically requires a kidney biopsy. MGRS subtypes are divided into 3 groups based on their pathologic findings: organized deposits, nonorganized deposits, and absence of immune deposits. Identifying the underlying clonal population of plasma cells or B cells is important to guide therapy. The standard of care for upfront treatment of light chain amyloidosis is daratumumab, cyclophosphamide, bortezomib, and dexamethasone. For other types of MGRS, the treatment depends on the underlying clone or the identified monoclonal protein. While light chain amyloidosis has validated response criteria, there are no uniform response criteria for other MGRS subtypes. Renal transplantation has been historically underutilized and represents a potentially transformative intervention in carefully selected patients who achieve good disease control using clone-directed therapy.

Hematologic malignancies are associated with an increased risk of venous thromboembolism (VTE) with aggressive lymphomas and multiple myeloma exhibiting the highest VTE incidence. The performance of VTE risk scores in hematologic malignancies remains suboptimal. Concomitant thrombocytopenia and coagulopathies complicate thrombosis prevention and management. This review synthesizes current evidence on anticoagulation in hematologic malignancies (excluding myeloproliferative neoplasms), outlines key clinical challenges, and proposes practical strategies to guide decision-making.

When acute lymphoblastic leukemia (ALL) involves extramedullary sites, the appropriate pathologic term for this is lymphoblastic lymphoma. The biological mechanisms underpinning this process are not clear, but they are presumed to involve a multifactorial interplay between tumor cells and the microenvironment of the tissue in which they develop (eg, lymph nodes, thymus, leptomeninges). Importantly for clinicians, these factors may impair the efficacy of systemic therapy given to treat ALL. This gives rise to "sanctuary sites," so named because of the relative protection they provide to malignant blasts that may possess these characteristics. This has become increasingly relevant in the era of "chemotherapy-free" approaches for B-cell ALL, where the potency of antigen-targeted immunotherapies (eg, blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor-modified T cells) has been leveraged to reduce or eliminate the reliance on cytotoxic chemotherapy. Such approaches are appealing for their high response rates and favorable toxicity profiles compared to chemotherapy. However, extramedullary relapses have been observed with increased frequency: an outcome historically seen in around 10% of such cases, this can represent over 50% of relapses in some series. This review provides an overview of this emerging issue and what clinicians and investigators can do to address it.

Indefinite maintenance therapy, typically with lenalidomide, remains a standard of care for patients with multiple myeloma, largely based on studies that demonstrated improved progression-free and overall survival compared to observation or placebo. However, these early trials often did not incorporate modern induction regimens or measurable residual disease (MRD) assessments. Despite newer induction regimens leading to high rates of MRD negativity, further intensification of maintenance remains the focus rather than de-escalation. As treatment paradigms have evolved to include quadruplet induction regimens and sensitive MRD assays, clinicians and patients increasingly question whether maintenance therapy can be safely stopped in selected individuals. This review examines the rationale for maintenance therapy, the historical data supporting its use, and emerging evidence from prospective studies suggesting that maintenance may be safely discontinued in patients with sustained multimodal MRD negativity. Patient-centered considerations, such as treatment-related toxicity, quality of life, and financial burden, underscore the importance of individualized decision-making regarding maintenance cessation. Also explored are future directions in MRD-guided treatment strategies, including de-escalation in the context of deep and sustained response. As the evidence base evolves, the challenge remains to balance the risks of indefinite therapy with the potential benefits of personalized, response-adaptive care in multiple myeloma.