Peripheral T-cell lymphomas (PTCLs) encompass a heterogeneous group of postthymic T-cell lymphomas with >30 distinct subtypes associated with varied clinicopathological features. Unfortunately, the overall survival of the major PTCL subtypes is dismal and has not improved for decades; thus, there is an urgent unmet clinical need to improve diagnosis, therapies, and clinical outcomes. The diagnosis is often challenging, requiring a combinatorial evaluation of clinical, morphologic, and immunophenotypic features. PTCL pathobiology is difficult to investigate due to enormous intertumor and intratumor heterogeneity, limited tissue availability, and the paucity of authentic T-cell lymphoma cell lines or genetically faithful animal models. The application of transcriptomic profiling and genomic sequencing has markedly accelerated the discovery of new biomarkers, molecular signatures, and genetic lesions, and some of the discoveries have been included in the revised World Health Organization or International Consensus Classification. Genome-wide investigations have revealed the mutational landscape and transcriptomic profiles of PTCL entities, defined the cell of origin as a major determinant of T-cell lymphoma biology, and allowed for the refinement of biologically and clinically meaningful entities for precision therapy. In this review, we prioritize the discussion on common nodal PTCL subtypes together with 2 virus-associated T-cell and natural killer cell lymphomas. We succinctly review normal T-cell development, differentiation, and T-cell receptor signaling as they relate to PTCL pathogenesis and biology. This review will facilitate a better biological understanding of the different PTCL entities and their stratification for additional studies and target-directed clinical trials.

Venous thromboembolism (VTE) is a common complication in patients with brain tumors. The management of acute VTE is particularly challenging due to an elevated risk of intracranial hemorrhage (ICH). Risk of developing ICH on anticoagulation is influenced by a number of factors including tumor type, recent surgery, concomitant medications, platelet counts, and radiographic features. In patients with a heightened risk for ICH, the benefits of anticoagulation need to be balanced against a likelihood of developing major hemorrhagic complications. Management decisions include whether to administer anticoagulation, at what dose, placement of an inferior vena cava filter, monitoring for development of hemorrhage or progressive thrombus, and escalation of anticoagulant dose. This article discusses the complexities of treating acute VTE in patients with brain tumors and outlines treatment algorithms based on the presence or absence of ICH at the time of VTE diagnosis. Through case-based scenarios, we illustrate our approach to anticoagulation, emphasizing individualized risk assessments and evidence-based practices to optimize treatment outcomes while minimizing the risks of hemorrhagic events in patients with brain tumors.

We performed an international retrospective study on 283 patients with light chain (AL) amyloidosis to investigate the prognostic impact of cytogenetic abnormalities by fluorescence in situ hybridization, when treated with frontline daratumumab-based therapy. The cytogenetic subgroups of interest were t(11;14), gain/amp(1q) (hereafter, +1q), hyperdiploidy, deletion(13q), del(17p), and myeloma high-risk (HR) translocations (t[4;14], t[14;16], or t[14;20]). The end points of interest were rate of hematologic complete response (heme-CR), very good partial response (VGPR) or better, and hematologic event-free survival (heme-EFS). The incidence of abnormalities was as follows: t(11;14), 53.4%; deletion (13q), 28.9%; +1q, 22.3%; hyperdiploidy, 19.4%; HR translocations, 6.6%; and deletion(17p), 4.5%. The heme-CR rate by cytogenetic subgroups were as follows: t(11;14) vs no t(11;14), 45.2% vs 41.8% (P=0.597); del(13q) vs no del(13q), 46.8% vs 42.8% (P=0.594); +1q vs no +1q, 30.2% vs 47.9% (P=0.022); hyperdiploidy vs no hyperdiploidy, 39.5% vs 44.9% (P=0.541); HR translocations vs none, 45.5% vs 43.1% (P=0.877); and del(17p) vs no del(17p), 50.0% vs 42.9% (P=0.658), respectively. Similarly, +1q was the only subgroup with a significantly lower VGPR or better rate (64.2% vs 79.0%; P=0.033). At a median follow-up of 19.8 months, the median heme-EFS was 49.6 months (95% CI, 24.7-not reached [NR]), and the 2-year overall survival (OS) was 80.98% (95% CI, 75.6-85.4). The presence of +1q was significantly associated with worse heme-EFS on multivariate analysis (HR 2.06, 95% CI, 1.14-3.71; P=0.017). Notably, there was no adverse prognostic impact of t(11;14) on heme-EFS or OS. In conclusion, +1q is associated with worse outcome in the daratumumab-era. Clinical trials testing novel frontline immunotherapies should be enriched in +1q to further improve outcomes in this subgroup.

Outcomes are poor in triple-class-exposed (TCE) relapsed and refractory multiple myeloma (R/RMM). In the phase 3 KarMMa-3 trial, patients with TCE R/RMM and 2 to 4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary end point; 13.3 vs 4.4 months; P < .0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median was 41.4 (95% CI, 30.9 to not reached [NR]) vs 37.9 (95% CI, 23.4 to NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI, 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE R/RMM. This trial was registered at www.ClinicalTrials.gov as #NCT03651128.

Using nanopore sequencing, we showed the feasibility and impact of rapid genomic screening for managing thrombotic microangiopathies in 18 prospective cases, achieving diagnoses in <3 days. We compared the results with standard exome sequencing, cost efficiency, and complement blockade initiation.

Immune thrombocytopenia (ITP) is a complicated bleeding disease characterized by a sharp platelet reduction. As a dominating element involved in ITP, megakaryocytes (MKs) are responsible for thrombopoiesis. However, the mechanism underlying the dysregulation of thrombopoiesis that occurs in ITP remains unidentified. In this study, we examined the role of Yes-associated protein 1 (YAP1) in thrombopoiesis during ITP. We observed reduced YAP1 expression with cytoskeletal actin misalignment in MKs from patients with ITP. Using an experimental ITP mouse model, we showed that reduced YAP1 expression induced aberrant MK distribution, reduced the percentage of late MKs among the total MKs, and caused submaximal platelet recovery. Mechanistically, YAP1 upregulation by binding of GATA-binding protein 1 to its promoter promoted MK maturation. Phosphorylated YAP1 promoted cytoskeletal activation by binding its WW2 domain to myosin heavy chain 9, thereby facilitating thrombopoiesis. Targeting YAP1 with its activator XMU-MP-1 was sufficient to rescue cytoskeletal defects and thrombopoiesis dysregulation in YAP1+/- mice with ITP and patients. Taken together, these results demonstrate the crucial role of YAP1 in thrombopoiesis, providing potential for the development of diagnostic markers and therapeutic options for ITP.

Hemostatic imbalances are frequent in patients with cancer. Although cancer-associated thrombotic complications have been well characterized, data on bleeding events in patients with cancer are sparse. Therefore, we aimed to investigate the incidence, risk factors, and impact on prognosis of bleeding events in patients with cancer initiating systemic anticancer therapies in a prospective cohort study, the Vienna Cancer, Thrombosis, and Bleeding Study. The primary study outcome was defined as clinically relevant bleeding (CRB), comprising major bleeding (MB) and clinically relevant nonmajor bleeding. In total, 791 patients (48% female), with median age of 63 years (interquartile range [IQR], 54-70), with various cancer types, 65.5% stage IV, were included. Over a median follow-up of 19 months (IQR, 8.7-24.0), we observed 194 CRB events in 139 (17.6%) patients, of which 42 (30.0%) were tumor related, 64 (46.0%) gastrointestinal, and 7 (5.0%) intracerebral. The 12-month cumulative incidence of first CRB and MB was 16.6% (95% confidence interval [CI], 13.7-19.6) and 9.1% (95% CI, 6.8-11.3), respectively, in the whole cohort, and 14.4% (95% CI, 11.2-17.5) and 7.0% (95% CI, 4.7-9.2), respectively, in those without anticoagulation. Patients with head and neck cancer had the highest risk of CRB. Lower baseline hemoglobin and albumin were associated with bleeding in patients without anticoagulation. Seven (5.0%) bleeding events were fatal, of which 6 occurred in patients without anticoagulation. Patients with CRB were at an increased risk of all-cause mortality (multivariable transition hazard ratio, 5.80; 95% CI, 4.53-7.43). In patients with cancer, bleeding events represent a frequent complication and are associated with increased mortality.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder driven by interferon gamma (IFN-γ). Emapalumab, an anti-IFN-γ antibody, is approved for the treatment of patients with primary HLH. Hematopoietic stem cell transplantation (HSCT) is required for curing HLH. Reduced-intensity conditioning (RIC) HSCT is associated with improved survival but higher incidences of mixed chimerism and secondary graft failure. To understand the potential impact of emapalumab on post-HSCT outcomes, we conducted a retrospective study of pediatric patients with HLH receiving a first RIC-HSCT at our institution between 2014 and 2022 after treatment for HLH, with or without this agent. Mixed chimerism was defined as <95% donor chimerism and severe mixed chimerism as <25% donor chimerism. Intervention-free survival (IFS) included donor lymphocyte infusion, infusion of donor CD34-selected cells, second HSCT, or death within 5 years after HSCT. Fifty patients met the inclusion criteria; 22 received emapalumab within 21 days before the conditioning regimen, and 28 did not. The use of emapalumab was associated with a markedly lower incidence of mixed chimerism (48% vs 77%; P = .03) and severe mixed chimerism (5% vs 38%; P < .01). IFS was significantly higher in patients receiving emapalumab (73% vs 43%; P = .03). Improved IFS was even more striking in infants aged <12 months, a group at the highest risk for mixed chimerism (75% vs 20%; P < .01). Although overall survival was higher with emapalumab, this difference was not significant (82% vs 71%; P = .39). We show that the use of emapalumab for HLH before HSCT mitigates the risk of mixed chimerism and graft failure after RIC-HSCT.

The association between antimetabolite dose intensity (DI) and adverse events among children receiving maintenance therapy for acute lymphoblastic leukemia (ALL) remains unclear, especially in the context of antimetabolite adherence. Using Children's Oncology Group AALL03N1 data, we examined the association between high DI during the first 4 study months and (i) treatment-related toxicities during the subsequent 2 study months; and (ii) relapse risk. Patients were classified into a high DI phenotype (either 6-mercaptopurine [6-MP] or methotrexate [MTX] DI ≥110% during the first 4 study months, or 6-MPDI or MTXDI 100%-110% at study enrollment and ≥25% increase over the 4 study months) and normal DI phenotype (all others). Only patients with wild-type TPMT and NUDT15 were included. 6-MP adherence data were available for 63.7% of study participants and used to stratify as adherent (median adherence ≥85%) and nonadherent (median adherence <85%) participants. Multivariable analyses were adjusted for sociodemographic and clinical prognosticators. Of the 644 patients, 29.3% were exposed to high DI. High DI was associated with a 2.1-fold greater odds of hematologic toxicity (95% confidence interval [CI] = 1.4-3.1; reference: normal DI) in the entire cohort and 2.9-fold higher among adherers (95% CI = 1.6-5.1); odds were comparable among nonadherers (2.1-fold; 95% CI = 0.4-10.1). Although high DI was not associated with relapse in the entire cohort (adjusted hazard ratio [aHR] = 1.4; 95% CI = 0.8-2.4), it was associated with a greater hazard of relapse among adherent participants (aHR = 2.4; 95% CI = 1.0-5.5) but not among nonadherent participants (aHR = 0.9; 95% CI = 0.2-3.8). Dose escalation above protocol doses during maintenance therapy for ALL should be done cautiously after assessing adherence to prescribed therapy.

Platelets contribute to a variety of physiological processes, including inflammation, sepsis, and cancer. However, because of their primary role in hemostasis, platelet transfusions are largely restricted to managing thrombocytopenia and bleeding. One way to expand the utility of platelet transfusions would be to genetically engineer donor platelets with new or enhanced functions. We have previously shown that lipid nanoparticles containing mRNA (mRNA-LNP) can be used to genetically modify authentic platelets in a nonclinical crystalloid solution. Currently, platelets collected for transfusion are stored in plasma or in plasma supplemented with platelet additive solution (PAS) at supraphysiological concentrations at room temperature, or at 4°C if intended for use in acute hemorrhage. Here, we describe a new plasma-optimized mRNA-LNP for transfecting platelets directly in plasma and plasma supplemented with PAS that is scalable to physiological and supraphysiological platelet concentrations. Transfecting platelets in clinical solutions with mRNA-LNP does not affect aspects of in vitro physiology, and transfected platelets are storable. The compatibility of this transfection system with current clinical practices could enable future mRNA-LNP-based platelet products and cell therapies.

Sickle cell disease (SCD) is canonically characterized by reduced red blood cell (RBC) deformability, leading to microvascular obstruction and inflammation. Although the biophysical properties of sickle RBCs are known to influence SCD vasculopathy, the contribution of poor RBC deformability to endothelial dysfunction has yet to be fully explored. Leveraging interrelated in vitro and in silico approaches, we introduce a new paradigm of SCD vasculopathy in which poorly deformable sickle RBCs directly cause endothelial dysfunction via mechanotransduction, during which endothelial cells sense and pathophysiologically respond to aberrant physical forces independently of microvascular obstruction, adhesion, or hemolysis. We demonstrate that perfusion of sickle RBCs or pharmacologically-dehydrated healthy RBCs into small venule-sized "endothelialized" microfluidics leads to pathologic physical interactions with endothelial cells that directly induce inflammatory pathways. Using a combination of computational simulations and large venule-sized endothelialized microfluidics, we observed that perfusion of heterogeneous sickle RBC subpopulations with varying deformability, as well as suspensions of dehydrated normal RBCs admixed with normal RBCs, leads to aberrant margination of the less-deformable RBC subpopulations toward the vessel walls, causing localized, increased shear stress. Increased wall stress is dependent on the degree of subpopulation heterogeneity and oxygen tension and leads to inflammatory endothelial gene expression via mechanotransductive pathways. Our multifaceted approach demonstrates that the presence of sickle RBCs with reduced deformability leads directly to pathological physical (ie, direct collisions and/or compressive forces) and shear-mediated interactions with endothelial cells and induces an inflammatory response, thereby elucidating the ubiquity of vascular dysfunction in SCD.

Teclistamab is a B-cell maturation antigen (BCMA)-directed bispecific antibody approved for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma (R/RMM). In the phase 1/2 MajesTEC-1 study, a cohort of patients who had prior BCMA-targeted therapy (antibody-drug conjugate [ADC] or chimeric antigen receptor T-cell [CAR-T] therapy) was enrolled to explore teclistamab in patients previously exposed to anti-BCMA treatment. At a median follow-up of 28.0 months (range, 0.7-31.1), 40 patients with prior BCMA-targeted therapy had received subcutaneous 1.5 mg/kg weekly teclistamab. The median prior lines of treatment was 6 (range, 3-14). Prior anti-BCMA therapy included ADC (n = 29), CAR-T (n = 15), or both (n = 4). The overall response rate was 52.5%; 47.5% of patients achieved very good partial response or better, and 30.0% achieved complete response or better. The median duration of response was 14.8 months, the median progression-free survival was 4.5 months, and the median overall survival was 15.5 months. The most common treatment-emergent adverse events (TEAEs) were neutropenia, infections, cytokine release syndrome, and anemia; cytopenias and infections were the most common grade ≥3 TEAEs. Infections occurred in 28 patients (70.0%; maximum grade 3/4, n = 13 [32.5%]; grade 5, n = 4 [10%]). Before starting teclistamab, baseline BCMA expression and immune characteristics were unaffected by prior anti-BCMA treatment. The MajesTEC-1 trial cohort C results demonstrate favorable efficacy and safety of teclistamab in patients with heavily pretreated R/RMM and prior anti-BCMA treatment. This trial was registered at www.ClinicalTrials.gov as #NCT03145181 and #NCT04557098.

Extramedullary disease (EMD) is a high-risk feature of multiple myeloma (MM) and remains a poor prognostic factor, even in the era of novel immunotherapies. Here, we applied spatial transcriptomics (RNA tomography for spatially resolved transcriptomics [tomo-seq] [n = 2] and 10x Visium [n = 12]) and single-cell RNA sequencing (n = 3) to a set of 14 EMD biopsies to dissect the 3-dimensional architecture of tumor cells and their microenvironment. Overall, infiltrating immune and stromal cells showed both intrapatient and interpatient variations, with no uniform distribution over the lesion. We observed substantial heterogeneity at the copy number level within plasma cells, including the emergence of new subclones in circumscribed areas of the tumor, which is consistent with genomic instability. We further identified the spatial expression differences between GPRC5D and TNFRSF17, 2 important antigens for bispecific antibody therapy. EMD masses were infiltrated by various immune cells, including T cells. Notably, exhausted TIM3+/PD-1+ T cells diffusely colocalized with MM cells, whereas functional and activated CD8+ T cells showed a focal infiltration pattern along with M1 macrophages in tumor-free regions. This segregation of fit and exhausted T cells was resolved in the case of response to T-cell-engaging bispecific antibodies. MM and microenvironment cells were embedded in a complex network that influenced immune activation and angiogenesis, and oxidative phosphorylation represented the major metabolic program within EMD lesions. In summary, spatial transcriptomics has revealed a multicellular ecosystem in EMD with checkpoint inhibition and dual targeting as potential new therapeutic avenues.