Hemophagocytic lymphohistiocytosis (HLH) is an interferon gamma-driven hyperinflammatory syndrome with high morbidity and mortality. Identifying reliable prognostic biomarkers is challenging due to various predisposing conditions and triggers. C-X-C-motif ligand 9 (CXCL9) is a clinically validated biomarker and surrogate marker of interferon gamma-mediated inflammation. We aimed to identify the role of CXCL9 in predicting severe disease and death in adults with HLH using a multicenter retrospective cohort of consecutively hospitalized patients who underwent a clinical evaluation for HLH that included CXCL9 testing. Patients were classified as HLH if they met HLH-2004 and/or HScore criteria. Conditional inference decision trees and Cox regression models were used to identify which clinical variables associated with acute mortality in patients with HLH. Overall, 171 patients were reviewed, and 126 patients met HLH criteria. The median age was 55 years (interquartile range, 40-66), with 62% male and 51% White. CXCL9 was markedly elevated in patients with HLH. Unbiased decision tree modeling, incorporating all clinical laboratory values, identified only CXCL9 of >16 100 pg/mL as the optimal predictor of inpatient mortality. Cox regression models demonstrated that CXCL9 of >16 100 pg/mL was significantly associated with 90-day mortality when controlling for important covariates. This shorter time to death in the elevated CXCL9 subgroup remained significant even after subdividing patients into those with malignancy (n = 53) and nonmalignancy HLH (n = 73). Continuous increases in CXCL9 within the cohort strongly associated with greater mortality. CXCL9 is a novel clinical marker that identifies high-risk HLH independent of underlying disease and could be used to select patients for early and aggressive targeted immunomodulatory therapy.

Recent studies have reached opposing conclusions about whether clonal hematopoiesis (CH) is increased or decreased in patients with sickle cell disease (SCD). Given that CH is typically age-related, its presence in children with SCD could offer unique insights into early-life mutagenesis and disease-related stressors. We tested the primary and secondary hypotheses that children with SCD would have a higher prevalence of CH than age-, sex-, and race-matched children without SCD and that children with hydroxyurea would have a higher CH prevalence than children not treated with hydroxyurea. To address this, we conducted a cross-sectional study in 2 independent cohorts of children aged 0 to 18 years with SCD (N = 1025 and N = 1293, respectively) and a 2957-person matched comparison group. Using a highly sensitive, error-corrected sequencing assay capable of detecting CH at a variant allele frequency of ≥0.5%, we found that children with SCD have a significantly higher prevalence of CH than the comparison group (odds ratio [OR], 4.2; P = 7.4 × 10-13). In addition, CH was not associated with exposure to hydroxyurea therapy (OR, 0.76; P = .44).

Immune checkpoint inhibitor-associated immune thrombocytopenia (ICI-ITP) has been described in case reports and small case series, but comprehensive data on its incidence, risk factors, clinical features, treatment, and outcomes are lacking. We reviewed medical records of all adults initiating ICI therapy between 2016 and 2023 at 29 US hospitals across 7 major cancer centers to identify patients with ICI-ITP. Multivariable logistic regression was used to identify risk factors, and Cox modeling was performed to assess the association between ICI-ITP, its severity, and mortality. Among 86 467 patients, ICI-ITP occurred in 214 (0.25%). Independent risk factors included lower baseline platelet count, combination ICI therapy, stage IV cancer, and additional immune-related adverse events. ICI-ITP occurred at a median of 8 weeks (interquartile range [IQR], 4-18) after ICI initiation, with a median nadir platelet count of 41 × 109/L (IQR, 17 × 109/L to 64 × 109/L). Patients were treated with glucocorticoids (n = 106 [49.5%]), immune globulin (n = 39 [18.2%]), and thrombopoietin receptor agonists (n = 29 [13.6%]). Recovery occurred in 161 patients (75.2%) at a median of 2.3 weeks (IQR, 1.0-5.3). Of 76 patients rechallenged with ICIs, 23 (30.3%) developed recurrent ICI-ITP. ICI-ITP and its severity were associated with higher all-cause mortality, with a nearly threefold increase in risk among patients with severe ICI-ITP than those without ICI-ITP (adjusted hazard ratio, 2.96 [95% confidence interval, 2.14-4.08]). These findings establish ICI-ITP as a rare but clinically significant complication of ICI therapy, provide, to our knowledge, the first large-scale description of its risk factors and clinical course, and underscore the importance of timely recognition and management.

In this review, we explore the role of complex interactions between genomic evolution, environmental and genetic predispositions, and immune surveillance in disease progression from precursor conditions smoldering multiple myeloma and monoclonal gammopathy of undetermined significance to multiple myeloma (MM). MM has been described to be universally preceded by precursor states, often decades before it is even diagnosed. Genetic predisposition plays an important role in the initial transformation, and is driven by both germline variants and MM-specific loci influencing risk. The reported disparities in occurrence of precursor conditions and MM among racial groups highlights the role of predisposition and the need for broader cohort studies. Early genomic events, such as translocations and hyperdiploidy, are essential in precursor initiation. However, additional factors are usually needed to transform the precursor stages into symptomatic disease, such as positive selection of subclonal populations. This process is affected by aging and environmental factors, such as exposures to Agent Orange and agrochemicals. Therefore, integrating genomic and transcriptomic data with immune profiling or other clinical features is essential for identifying patients with high risk of progressing into MM. Here, we highlight the complexity of myelomagenesis, and underline the importance of state-of-the-art approaches for improved disease prediction.

Measurable residual disease (MRD) can predict relapse in patients with advanced myelodysplastic neoplasms (MDS) or acute myeloid leukemia (AML). We report the long-term efficacy and safety of MRD-guided preemptive azacitidine treatment to prevent relapse in the phase 2 Relapse Prevention With Azacitidine (RELAZA2) trial. Patients with MDS or AML after either intensive chemotherapy only or consecutive allogeneic stem cell transplantation were prospectively screened for imminent relapse by molecular MRD assessment. Patients who became MRD positive (MRDpos) during screening received azacitidine for up to 2 years to prevent relapse. The primary end point was the proportion of patients alive and relapse-free 6 months after azacitidine start. Of 357 patients screened, 119 (33.3%) became MRDpos, of whom 95 (79.8%) were eligible for azacitidine treatment. The primary end point was met; 60 (63%) patients were relapse free (95% confidence interval, 54-71; P< .0001) 6 months after azacitidine initiation with no new safety signals. Of 60 patients achieving MRD response during the first 6 cycles of azacitidine, 31 (52%) maintained response without hematological relapse for ≥2 years after azacitidine initiation. The median treatment-free duration after azacitidine discontinuation was 20.8 months; the longest ongoing response was 104 months. After a median follow-up of 6.6 years, 15 initial responders (25%) remained alive and in remission. Among screened patients who remained continuously MRD negative, 60-month overall survival and relapse-free survival were 88% and 79%, respectively. Patients with continuously negative MRD display a very favorable prognosis. Most patients with MRD positivity can be effectively treated with azacitidine with potential long-term remission even after termination of azacitidine. This trial was registered at www.clinicaltrials.gov as #NCT01462578.

Marstacimab, a monoclonal antibody that inhibits tissue factor pathway inhibitor, is approved for prophylactic use in individuals with hemophilia A or B without inhibitors. We present efficacy and safety for individuals with inhibitors. The open-label, single-arm, phase 3 study evaluated once-weekly subcutaneous flat-dose marstacimab in males aged 12 to <75 years with severe hemophilia A or moderately severe to severe hemophilia B. Participants with inhibitors received bypassing agents (on-demand or routine prophylaxis) during a 6-month observational phase (OP) before entering a 12-month active treatment phase (ATP) with marstacimab. Primary end points were annualized bleeding rate (ABR) of treated bleeds and safety. Of 60 participants with inhibitors in the OP, 51 entered the ATP and received marstacimab. In the on-demand group (n = 48), mean estimated ABR declined from 19.78 (95% confidence interval [CI], 16.12-24.27) in the OP to 1.39 (95% CI, 0.85-2.29) during the ATP (ABR ratio, 0.07 [95% CI, 0.042-0.118]; 2-sided P< .0001). Results were consistent by hemophilia type (ABR ratio, 0.05 [hemophilia A, n = 40]; 0.13 [hemophilia B, n = 8]). Participants reported significant improvements in health-related quality of life. Adverse events were common but mostly mild; 1 treatment-related grade 3 skin rash led to discontinuation. Antidrug antibodies were detected in 19.6% of participants, with no apparent effect on efficacy or safety. In participants with inhibitors, marstacimab was associated with reduced bleeding rates and an acceptable safety profile, with no thromboembolic events. Marstacimab may be a viable treatment option for people with hemophilia A or B with inhibitors. This trial was registered at www.clinicaltrials.gov as #NCT03938792. ClinicalTrials.gov identifier: NCT03938792.

We assessed the overall survival (OS) impact of time to relapse (TTR) in multinational cohorts with independent observational and randomized validation. Patients with nMTCL with frontline complete response were assigned to TTR12 (≤12 months) or without TTR12 based on time to progression or next therapy. OS analyses included modified landmark (m-LM), standard landmark (s-LM), and time-dependent Cox (td-Cox), adjusting for age, histology, and prognostic index for T-cell lymphoma (PIT) score. Across 452 patients, 165 (36.5%) had TTR12, 181 (40%) relapsed at ≥12 months, and 106 (23.5%) remained relapse-free. TTR12 conferred worse OS using m-LM (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.58-2.90; P< .001), s-LM (HR, 1.92; 95% CI, 1.39-2.66; P< .001); and td-Cox (HR, 5.81; 95% CI, 2.94-11.46; P< .001). Results were consistent in the independent validation cohorts. TTR12 consistently conferred worse OS irrespective of frontline stem cell transplantation or PIT score, in peripheral T-cell lymphoma, not otherwise specified (m-LM: HR, 2.32; 95% CI, 1.51-3.55; P< .001; s-LM: HR, 2.10; 95% CI, 1.33-3.31; P = .001), anaplastic large cell lymphoma (m-LM: HR, 3.34; 95% CI, 1.18-9.50; P = .023; s-LM: HR, 2.96; 95% CI, 1.02-8.81; P = .046), and angioimmunoblastic T-cell/T follicular helper cell lymphoma (m-LM only: HR, 1.92; 95% CI, 1.15-3.21; P = .013). Second-line novel therapies improved OS (second-line start to death) vs chemotherapy in TTR12 only (HR, 0.60; 95% CI, 0.37-0.97; P = .038; without TTR12: HR, 0.82; 95% CI, 0.51-1.32; P = .407). TTR12 serves as a prognostic and potential OS surrogate marker, supporting stratification of new risk groups and need for their differential treatment.

The phase 1/2 BelaRd (belantamab mafodotin [belamaf], lenalidomide, and dexamethasone) study evaluated the efficacy and safety of belamaf combined with lenalidomide and dexamethasone in unfit and frail transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Part 1 (n = 36) established a recommended belamaf phase 2 dose (RP2D) of 1.9 mg/kg every 8 weeks (median follow-up, 39.3 months). In part 2, 30 patients were randomized 1:1 in group A (n = 15), where belamaf dosing was guided by ophthalmologist-assessed ocular adverse events (OAEs), whereas in group B (n = 15), belamaf dosing was based on hematologist-led vision-related anamnestic (VRA) tool and ophthalmologist-assessed grade ≥3 OAEs. Among the RP2D patients (n = 42), overall response rate was 97.6%, median progression-free survival (PFS)/overall survival have not been reached yet, and the 18-month PFS and time to progression rates were 83.0% and 97.2%, respectively. Ocular toxicities were similar between assessments by hematologists and ophthalmologists, and no ophthalmologist withholding of a hematologist-led dosing occurred. Less than 1% of patients stopped driving/reading because of OAEs. Median time to belamaf reinfusion was 13 weeks. Overall, BelaRd is an effective regimen for transplant-ineligible patients with NDMM and warrants a phase 3 study in this setting. OAEs' impact on quality of life appears limited, and implementation of the hematologist-led VRA tool may eventually reduce the necessity for ophthalmologist assessments. This trial was registered at www.clinicaltrials.gov as #NCT04808037.

Neutrophils, critical components of innate immunity, undergo significant morphological changes during phagocytosis. In this study, we demonstrate that neutrophils exposed to shear stress generate lipid nanotubes (NTs) with a unique composition. Compared with the proteome of whole neutrophils, NTs notably lack cytoskeletal elements and the complement-inhibiting transmembrane protein CD46. Consequently, these NTs are recognized by the complement system and selectively opsonized the complement component C3b. Biophysical characterization of NTs confirmed that their integrity relies on lipid-lipid interactions and that they pinch off from neutrophils to form NT-derived vesicles (NTDVs). We detected C3b+ NTDVs in plasma from patients and animal models experiencing diverse inflammatory conditions, including metastatic melanoma, vasculitis, and polytrauma. Further functional experiments indicate that resting neutrophils phagocytose complement-opsonized NTDVs, leading to cell activation, including the production of reactive oxygen species. In conclusion, our data suggest a significant role for neutrophil-derived NTs in a wide range of inflammatory diseases and reveal a previously unknown mode of cell-cell communication.