Among 64 patients with Erdheim-Chester disease treated with a BRAF inhibitor (median follow-up 4 years), we found high response rates (85%) but frequent discontinuations (61%), primarily because of adverse events. Additionally, patients experienced poor health-related quality of life and high symptom burden.

Fitusiran, a subcutaneous investigational siRNA therapeutic, lowers antithrombin (AT) to increase thrombin generation and rebalance hemostasis in people with hemophilia. This phase 3 open-label extension study (ATLAS‑OLE, NCT03754790) evaluated safety and efficacy of antithrombin-based dose regimen (AT-DR) in males ≥ 12 years with severe hemophilia A/B, with/without inhibitors. The original 80 mg monthly (QM) dose regimen (ODR) was optimized to AT-DR targeting AT activity levels 15-35% to mitigate thrombotic risk (starting dose 50 mg once every 2 months [Q2M], individually adjusted to 20 mg Q2M or 20/50/80 mg QM as needed). Primary and secondary endpoints were safety and efficacy, respectively. Integrated safety analyses assessed safety of AT-DR and ODR across all fitusiran studies and integrated efficacy analyses compared efficacy of AT‑DR in ATLAS‑OLE with phase 3 parent study control groups. At interim data cut-off, 213 participants were enrolled on AT-DR (78% on Q2M regimens). Integrated safety analyses of participants receiving AT-DR (n = 286) demonstrated that AT-DR was well tolerated. In ATLAS-OLE, median (interquartile range) observed annualized bleeding rate (ABR) with AT-DR was 3.7 (0.0, 7.5). Integrated efficacy analyses demonstrated superiority of AT-DR over on-demand clotting factor concentrates (CFCs) (71% mean ABR reduction, P < 0.0001), and on-demand bypassing agents (BPAs) (73% mean ABR reduction, P = 0.0006); improvement over BPA prophylaxis (70% mean ABR reduction); and comparable ABR to CFC prophylaxis. Fitusiran AT‑DR was well tolerated and maintained bleed protection with as few as 6 injections per year. This trial was registered at www.clinicaltrials.gov as #NCT03754790.

Overall survival (OS) and quality of life (QoL) are clinically relevant outcomes/endpoints during examination of therapies. However, with median OS approaching 20 years for patients with follicular lymphoma (FL), it is often not feasible to use OS as a primary endpoint in clinical studies. While validated tools for assessing QoL in patient with lymphoma exist, QoL data are rarely the sole basis for drug approvals in FL. Therefore, other survival endpoints, surrogates, and intermediate clinical endpoints have all been used to measure outcomes in FL trials. In this review, we discuss the strengths and limitations of these commonly used traditional endpoints in FL trials and examine the current gaps, including delayed availability of results and suboptimal sensitivity in distinguishing difference in therapeutic effects. To help address the gaps identified, well-validated surrogates, such as complete remission 30 months after starting frontline immunochemotherapy (CR30), may be used as the primary or co-primary endpoint in confirmatory randomized trials. Emerging intermediate endpoints like minimal residual disease, may be useful in early phase trials and in guiding accelerated approvals after appropriate validation. As patient preference plays a crucial role in treatment decisions in FL, it is critical to include QoL as an important secondary trial endpoint and to measure non-medical burdens, including time and financial toxicities. Endpoints that are clinically relevant, timely, and patient-centered may identify new drugs that help patients with FL live longer and better lives.

Progress in the therapy of follicular lymphoma (FL), the most common indolent lymphoma subtype, has been achieved in recent years with significant improvement in median overall survival. Most patients diagnosed with FL will now die from other causes. Multiple novel immunotherapy and other targeted therapies are now approved for relapsed and refractory disease. However, early progression and transformation to aggressive lymphoma remain key issues requiring further innovation. We expect that bispecific antibodies will likely move to earlier use and in novel combinations. Future generations of these and chimeric antigen receptor T-cell therapy will be developed in an effort to minimize toxicity and improve efficacy. New technologies, such as circulating tumor DNA assays, may enable more rational selection and guidance of therapy duration or changes in treatment, as well as possibly substituting for follow up imaging while monitoring patients. We also look forward to more extensive use of quality of life tools to select treatment in patients who have a favorable long-term outlook with multiple options. Finally, patients and clinicians now envision a day when FL is no longer referred to as "incurable". Having a definition and possibility of a "cure" and being able to optimize such a mindset in the approach of FL would represent a major advance in our future management strategy.

Thrombus structure and composition are the main determinants of the severity, course, and outcomes of thrombosis. Detailed thrombus morphology has become available due to mechanical thrombectomy, which allows extraction of fresh thrombi from patients followed by scanning electron microscopy. The major structural elements of a thrombus are platelets, erythrocytes, and fibrin, each playing a critical role in determination of biological and physical properties of thrombi, such as permeability, stiffness, lytic and mechanical stability. The minor components include neutrophils, monocytes, von Willebrand factor, cellular microvesicles, plasma proteins, cholesterol crystals, and other structures. Platelets are responsible for contraction (retraction) of thrombi, which results in compaction with very little free space, low permeability and high stiffness. Because of clot contraction, erythrocytes, which are prevalent in all types of thrombi, undergo compressive deformation to polyhedral (polyhedrocytes) and polyhedral-like cells, altogether comprising pressure-deformed cells (piezocytes). Fibrin is the structural and mechanical scaffold of thrombi that changes in time and space both quantitatively and qualitatively during their formation. Fibrin is an equilibrium polymer that can adapt to forced deformations by reorientation at the microscopic level and unfolding at the molecular level. The relative volume fractions of thrombus components, their functional and structural forms vary substantially, providing a basis for the diverse pathogenic mechanisms and clinical manifestations of thrombosis. Modulating any of the components lead to prospective therapeutic approaches. This review summarizes recent research that describes quantitative and qualitative morphologic characteristics of arterial and venous thrombi that provide a basis for new therapeutic opportunities in thrombosis.

Natural killer (NK) cells are important effector cells in antibody-based immune therapies for multiple myeloma (MM) through antibody-dependent cellular cytotoxicity. Here, we used single-cell transcriptomics, flow cytometry and functional assays to investigate the bone marrow NK cell compartment of MM patients at diagnosis and during treatment. We show reduced proportion of CD16+ cytotoxic NK cells in a subset of patients at diagnosis, which correlated with decreased cytokine production and NK cell degranulation against MM cells in the presence of the anti-CD38 antibody daratumumab. In line with these findings, a low proportion of CD16+ bone marrow NK cells at diagnosis was associated with a reduced likelihood of achieving MRD-negativity post-consolidation in patients treated with daratumumab, bortezomib, thalidomide and dexamethasone in conjunction with autologous stem cell transplantation in the CASSIOPEIA trial. In contrast, NK cell distribution did not predict MRD-negativity in patients treated in the control arm without daratumumab. These findings highlight the impact of the bone marrow NK cell compartment on therapeutic outcomes in MM patients receiving immunotherapy with CD38-targeting antibodies.

Although the bone marrow is the main site of blood cell production in adults, rare pools of hematopoietic stem and progenitor cells have been found in extramedullary organs. In mice, we have previously shown that the lung contains hematopoietic progenitor cells and is a site of platelet production. Here, in the adult human lung, we show that functional hematopoietic precursors reside in the extravascular spaces with a frequency similar to the bone marrow and are capable of proliferation and engraftment in mice. The gene signature of pulmonary and medullary CD34+ hematopoietic progenitors indicates greater baseline activation of immune-, megakaryocyte/platelet-, and erythroid-related pathways in lung progenitors. Spatial transcriptomics mapped blood progenitors in the lung to an alveolar interstitium niche with only a few cells identified in an intravascular location. In human blood samples collected for stem cell transplantation, CD34+ cells with a lung signature enriched the mobilized pool of hematopoietic stem cells. These results identify the lung as a pool for uniquely programmed blood stem and progenitor cells with the potential to support hematopoiesis in humans.