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Holden Schack posted an update 8 months, 1 week ago
Several targeted agents have proven effective, but the majority do not produce durable responses, requiring development in combination with other targeted or conventional therapies. Herein, promising targets in aggressive lymphoma with the greatest potential for improving outcomes in these patients are discussed. Novel therapies, their toxicities, and their potential role in initial or subsequent treatment are highlighted.Recurrent venous thromboembolism (VTE, or deep vein thrombosis and pulmonary embolism) is associated with mortality and long-term morbidity. The circumstances in which an index VTE event occurred are crucial when personalized VTE recurrence risk is assessed. Patients who experience a VTE event in the setting of a transient major risk factor (such as surgery associated with general anesthesia for >30 minutes) are predicted to have a low VTE recurrence risk following discontinuation of anticoagulation, and limited-duration anticoagulation is generally recommended. In contrast, those patients whose VTE event occurred in the absence of risk factors or who have persistent risk factors have a higher VTE recurrence risk. Here, we review the literature surrounding VTE recurrence risk in a range of clinical conditions. We describe gender-specific risks, including VTE recurrence risk following hormone- and pregnancy-associated VTE events. Finally, we discuss how the competing impacts of VTE recurrence and bleeding have shaped international guideline recommendations.CD38 antibodies were first evaluated in extensively pretreated patients with multiple myeloma (MM). Currently, there are 3 CD38 antibody-based regimens approved for the treatment of both transplant-eligible (daratumumab plus bortezomib-thalidomide-dexamethasone ) and transplant-ineligible (daratumumab plus lenalidomide-dexamethasone or daratumumab plus bortezomib-melphalan-prednisone ) patients with newly diagnosed MM (NDMM). The phase 3 studies that evaluated these regimens uniformly showed that the addition of daratumumab to backbone regimens improved the depth of response, which translated into improved progression-free survival and also overall survival in 2 of the studies. Importantly, elderly patients age 75 years or older benefit from these regimens, indicating that these regimens have an acceptable safety profile. Although the number of patients with high-risk cytogenetics was relatively small, these patients also experienced benefit from the addition of daratumumab to standard-of-care regimens, but poor risk conferred by the cytogenetic aberrations is not completely abrogated. Altogether, daratumumab-based regimens have high anti-MM activity and a favorable toxicity profile and therefore represent new standards of care for patients with NDMM.Despite recent advances in treatment, relapses in multiple myeloma (MM) are inevitable. Off-the-shelf immunotherapeutics represent a promising avenue for research, with various classes of agents under development and several demonstrating deep and durable responses in patients who have exhausted all available therapies. Antibody-drug conjugates (ADCs) seek to improve on naked monoclonal antibodies by delivering a cytotoxic payload directly to tumor cells while largely limiting systemic effects. Belantamab mafodotin, a B-cell maturation antigen (BCMA)-targeted ADC, has shown response rates >30% in a phase 2 trial of highly refractory patients and is being investigated in a variety of settings and combinations. Several other ADCs are in earlier stages of development that target cell surface antigens that are internalized, including BCMA, CD38, CD46, CD56, CD74, and CD138. Bispecifics are designed to bring cytotoxic immune effector cells into proximity with tumor cells, and several agents have shown high response rates in early trials. Current targets include BCMA, CD38, GPRC5d, and FCRH5, and all of these seek to engage T cells through CD3. Bispecifics targeting natural killer (NK) cells through CD16 are still in preclinical development. Trispecific antibodies may represent an advance over bispecifics by providing a T-cell costimulatory signal such as CD28, or alternatively, dual MM antigens to increase specificity of NK or T-cell targeting. This is an area of active preclinical research at this time. Lastly, designed ankyrin repeat proteins, which are small antibody-mimetic proteins with high target-binding affinity, have the potential to block multiple pathways at once and provide stimulatory signals to the immune system.The short telomere syndromes encompass a spectrum of clinical manifestations that present from infancy to late adulthood. They are caused by mutations in telomerase and other telomere maintenance genes and have a predominantly degenerative phenotype characterized by organ failure across multiple systems. They are collectively one of the most common inherited bone marrow failure syndromes; however, their most prevalent presentations are extrahematopoietic. This review focuses on these common nonhematologic complications, including pulmonary fibrosis, liver pathology, and immunodeficiency. The short telomere syndrome diagnosis informs clinical care, especially in guiding diagnostic evaluations as well as in the solid organ transplant setting. Early recognition allows an individualized approach to screening and management. This review illustrates a myriad of extrahematopoietic presentations of short telomere syndromes and how they impact clinical decisions.The Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) are a heterogenous group of hematopoietic stem cell diseases characterized by activated JAK/STAT signaling and a variable propensity toward myelofibrotic and leukemic transformation. Acquisition of somatic mutations in addition to the canonical JAK2, MPL, and CALR mutations found in MPNs is an important catalyst in the clonal evolution and progression of these disorders. In recent years, our increasing understanding of the molecular landscape of Ph- MPNs has generated important prognostic information that informs our approach to risk stratification and therapeutic decision-making. selleck This review will focus on the critical impact of genomics on our approach to management of advanced Ph- MPNs.
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