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

Targeted therapy is a powerful treatment option in chronic lymphocytic leukemia (CLL) that has outperformed conventional chemoimmunotherapy in most clinical settings. Except for selected young, fit patients with a mutated immunoglobulin heavy chain variable region gene, most patients benefit from targeted therapy with either a continuous BTK inhibitor or 1-year fixed-duration venetoclax-obinutuzumab as first-line treatment of CLL. Treatment selection is driven by patient-, treatment-, and disease-related factors, encompassing patient preference, concomitant medications, comorbidities, safety profile of the regimen, and TP53 aberration. Clinical trials are actively investigating the simultaneous inhibition of Bruton's tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) proteins with or without a CD20 monoclonal antibody, which can achieve deep response in most patients (52%-89% undetectable minimal residual disease in bone marrow).

Richter's syndrome (RS) is an aggressive histologic transformation of chronic lymphocytic leukemia (CLL), most commonly to diffuse large B-cell lymphoma (DLBCL). Outcomes are generally poor, with complete remission (CR) rates of only about 20% and less than 20% long-term survival with chemoimmunotherapy (CIT). RS is biologically heterogeneous, and in 80% of patients with CLL who develop DLBCL, the disease is clonally related to the CLL. Clonally unrelated cases are genetically and immunologically distinct from clonally related DLBCL-RS, have more favorable responses to CIT, and are best treated as de novo DLBCL. Relatively favorable outcomes with CIT are also seen in patients who have never previously received treatment for CLL and who lack TP53 mutation or deletion. For the remaining patients, treatment on a clinical trial is optimal. Fortunately, numerous agents are now in clinical development that show encouraging results. Here we review clinical data for some of the most promising approaches. DLBCL-RS tumor cells frequently express programmed cell death 1 protein (PD-1), and several studies have demonstrated activity for PD-1 inhibitors, especially in combination with ibrutinib. The BCL2 inhibitor venetoclax in combination with R-EPOCH CIT achieved CR in 50% of patients, and a study of venetoclax-R-CHOP is ongoing. The noncovalent Bruton's tyrosine kinase inhibitor pirtobrutinib has achieved responses in approximately two-thirds of heavily pretreated patients and, given its favorable toxicity profile, appears ideally suited to combining with other active agents. Finally, we review available data for bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor T-cell therapy, which, after revolutionizing the treatment of DLBCL, are now being evaluated in RS.

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.

Discussions regarding gonadal function and possible disease or treatment-related ovarian or testicular dysfunction, sexual dysfunction, and possible future infertility can be challenging in the sickle cell disease (SCD) pediatric care setting. A construct that stratifies topics into those that are time sensitive and those that require reproductive care expertise vs address gonadal health as a part of normal SCD care may be helpful. Pediatric health care discussions of gonadal function/dysfunction for patients with SCD can include (1) time-sensitive fertility consults preceding the start of gonadotoxic therapy and (2) targeted discussions at key time points during normally scheduled hematology clinic visits. The former conversations are best led by individuals with expertise in the risk for treatment-related infertility and fertility preservation. The latter discussions can be incorporated into targeted regularly scheduled visits with hematologists. These topics can be addressed as a part of planned education in pediatric care for adolescents and incorporated into transition plans as young adults transfer care to adult providers. Although the topics of puberty and gonadal health can be uncomfortable and many complex interdisciplinary and ethical issues arise in this process, these discussions can be aided by the collaterals and teaching handouts presented in this article.

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.