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

The standard approach to treatment of primary refractory/first relapse of classical Hodgkin lymphoma (cHL) is administration of second-line therapy (SLT) followed by consolidation with high-dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). Historically, this approach cured about 50% of patients. Due to improvements in supportive care, positron emission tomography-adaptive strategies, and incorporation of novel agents into SLT, contemporary studies show that about 75% of patients with primary refractory or first relapse of cHL can be cured. Recent studies evaluating incorporation of PD-1 blockade in SLT appear to show even further improvement in remission rates and bring into question whether an aggressive approach that includes HDT/AHCT is needed for everyone. To address this question, several ongoing studies are beginning to explore the possibility of avoiding or delaying HDT/AHCT for patients with primary refractory or first relapse of cHL.

The therapeutic landscape in multiple myeloma (MM) has changed dramatically over the last 2 decades. With the introduction of novel immunotherapies, patients with MM can expect deeper responses, longer remissions, and improved overall survival. Since its approval by the US Food and Drug Administration in 2015, the monoclonal antibody specific for CD38, daratumumab, has been incorporated into both frontline and relapsed treatment regimens. Its role as a maintenance therapy is currently being explored. Subsequently, a variety of novel antibody therapeutics have evolved from the success of daratumumab, using similar concepts to target the malignant plasma cell clone. Noteworthy naked monoclonal antibodies include isatuximab, another agent directed against CD38, and elotuzumab, an agent directed against SLAM family member 7. Antibody-drug conjugates, complex molecules composed of an antibody tethered to a cytotoxic drug, target malignant cells and deliver a lethal payload. The first to market is belantamab mafodotin, which targets B-cell maturation antigen (BCMA) on malignant plasma cells and delivers a potent microtubule inhibitor, monomethyl auristatin F. Additionally, bispecific T-cell antibodies are in development that engage the immune system directly by simultaneously binding CD3 on T cells and a target epitope-such as BCMA, G-protein coupled receptor family C group 5 member D (GPRC5d), and Fc receptor homologue 5 (FcRH5)-on malignant cells. Currently, teclistamab, an anti-BCMA bispecific, is closest to approval for commercial use. In this review, we explore the evolving landscape of antibodies in the treatment of MM, including their role in frontline and relapse settings.

Patients with multiple myeloma (MM) have up to a 20-fold increased risk of venous thromboembolism (VTE) compared with the general population, with most events occurring within the first 6 months of diagnosis. Treatment with immunomodulatory drugs (IMiDs) is a strong risk factor for VTE in MM. In a meta-analysis of 2 large, randomized trials comparing anticoagulant thromboprophylaxis vs placebo in ambulatory patients with cancer at high risk of VTE based on a validated risk score, the risk of VTE decreased without increasing the risk of major bleeding. However, few patients with MM participated in these trials (1.1%). Initial guidance for risk-stratifying patients with MM resulted in persistent rates of VTE >10% and highlighted the need for improved VTE risk stratification in patients with MM. Three validated risk scores are now available to quantify risk of VTE in patients with MM: SAVED, IMPEDE VTE, and PRISM scores. Using best available data, thromboprophylaxis should be strongly considered in patients with MM assessed as high risk for VTE, especially newly diagnosed patients receiving IMiD-based combination therapies. However, prospective studies are needed to further validate available models and identify the optimal thromboprophylactic agent for each VTE risk category.

The BCR-ABL-negative myeloproliferative neoplasms (MPNs) have a variable risk of progressing to accelerated- or blast-phase MPN (MPN-AP/MPN-BP), defined by the presence of 10% to 19% and more than or equal to 20% myeloid blasts in the peripheral blood or bone marrow, respectively. The molecular processes underlying the progression to MPN-AP/MPN-BP are becoming increasingly understood with the acquisition of additional mutations in epigenetic modifiers (eg, ASXL1, EZH2, TET2), TP53, the Ras pathway, or splicing factors (eg, SRSF2, U2AF1), having been described as important steps in this evolutionary process. At least partially driven by the enrichment of these high-risk molecular features, the prognosis of patients with MPN-BP remains inferior to other patients with acute myeloid leukemia, with a median overall survival of 3 to 6 months. Allogeneic hematopoietic cell transplantation remains the only potentially curative therapeutic modality, but only a minority of patients are eligible. In the absence of curative intent, therapeutic strategies or palliative treatment with hypomethylating agents as monotherapy or in combination with ruxolitinib or venetoclax can be considered. Several novel agents are in various stages of clinical development but are not available for routine use at this point, highlighting the need for ongoing research and the prioritization of clinical trial enrollment when feasible.

The field of thromboprophylaxis for acutely ill medical patients, including those hospitalized for COVID-19, is rapidly evolving both in the inpatient setting and the immediate post-hospital discharge period. Recent data reveal the importance of incorporating holistic thromboembolic outcomes that encompass both venous thromboembolism (VTE) and arterial thromboembolism, as thromboprophylaxis with low-dose direct oral anticoagulants has been shown to reduce major and fatal vascular events, especially against a background of dual pathway inhibition with aspirin. In addition, recent post hoc analyses from randomized trial data have established 5 key bleeding-risk factors that, if removed, reveal a low-bleeding- risk medically ill population and, conversely, key individual risk factors, such as advanced age, a past history of cancer or VTE, an elevated D-dimer, or the use of a validated VTE risk score-the IMPROVE VTE score using established cutoffs-to predict a high-VTE-risk medically ill population that benefits from extended postdischarge thromboprophylaxis. Last, thromboprophylaxis of a high-thrombotic-risk subset of medically ill patients, those with COVID-19, is rapidly evolving, both during hospitalization and post discharge. This article reviews 3 controversial topics in the thromboprophylaxis of hospitalized acutely ill medical patients: (1) clinical relevance of key efficacy and safety outcomes incorporated into randomized trials but not incorporated into relevant antithrombotic guidelines on the topic, (2) the use of individual risk factors or risk models of low-bleeding-risk and high-thrombotic-risk subgroups of medically ill inpatients that benefit from extended thromboprophylaxis, and (3) thromboprophylaxis of hospitalized COVID-19 patients, including extended postdischarge thromboprophylaxis.

Multiple studies have demonstrated that patients with acute myeloid leukemia (AML) who have measurable residual disease (MRD) detected during or after treatment have higher relapse rates and worse survival than similar patients testing negative. Updated response criteria for AML reflect the understanding that achievement of complete remission (CR) with no detectable MRD using high-sensitivity tests represents a superior response over conventional cytomorphological CR alone. Potential use cases for AML MRD testing are diverse and include patient selection for clinical trials and therapeutic assignment, early relapse detection and intervention during sequential monitoring, and drug development, including deep quantification for antileukemia efficacy and as a surrogate endpoint for overall survival in regulatory approvals. Testing for AML MRD has not, however, been harmonized, and many technical and clinical questions remain. The implications of MRD test results for specific therapeutic combinations, molecular subsets, test types, treatment time points, sample types, and patient characteristics remain incompletely defined. No perfect AML MRD test or testing strategy currently exists, and the evidence basis for clinical recommendations in this rare disease is sparse but growing. It is unproven whether conversion of an MRD test result from positive to negative by additional therapeutic intervention improves relapse risk and survival. Several national- and international-level consortia have recently been initiated to advance the generation and collection of evidence to support the use of AML MRD testing in clinical practice, drug development, and regulatory approvals.

The serologic evaluation of autoimmune hemolytic anemia (AIHA) confirms the clinical diagnosis, helps distinguish the type of AIHA, and identifies whether any underlying alloantibodies are present that might complicate the selection of the safest blood for any needed transfusion. The spectrum of testing is generally dependent on the amount and class (immunoglobulin G or M) of autoantibody as well as the resources and methodologies where testing is performed. The approach may range from routine pretransfusion testing, including the direct antiglobulin test, to advanced techniques such as adsorptions, elution, and red cell genotyping. When transfusion is needed, the selection of the optimal unit of red blood cells is based on urgency and whether time allows for the completion of sophisticated serologic and molecular testing methods. From the start of when AIHA is suspected until the completion of testing, communication among the clinical team and medical laboratory scientists in the transfusion service and immunohematology reference laboratory is critical as testing can take several hours and the need for transfusion may be urgent. The frequent exchange of information including the patient's transfusion history and clinical status, the progress of testing, and any available results is invaluable for timely diagnosis, ongoing management of the patient, and the safety of transfusion if required before testing is complete.

Anticoagulants have been in use for nearly a century for the treatment and prevention of venous and arterial thromboembolic disorders. The most dreaded complication of anticoagulant treatment is the occurrence of bleeding, which may be serious and even life-threatening. All available anticoagulants, which target either multiple coagulation factors or individual components of the tissue factor (TF) factor VIIa or the common pathways, have the potential to affect hemostasis and thus to increase bleeding risk in treated patients. While direct oral anticoagulants introduced an improvement in care for eligible patients in terms of safety, efficacy, and convenience of treatment, there remain unmet clinical needs for patients requiring anticoagulant drugs. Anticoagulant therapy is sometimes avoided for fear of hemorrhagic complications, and other patients are undertreated due to comorbidities and the perception of increased bleeding risk. Evidence suggests that the contact pathway of coagulation has a limited role in initiating physiologic in vivo coagulation and that it contributes to thrombosis more than it does to hemostasis. Because inhibition of the contact pathway is less likely to promote bleeding, it is an attractive target for the development of anticoagulants with improved safety. Preclinical and early clinical data indicate that novel agents that selectively target factor XI or factor XII can reduce venous and arterial thrombosis without an increase in bleeding complications.