Citations

Background Radionuclide SPECT/computed tomography (CT) is standard for diagnosing transthyretin cardiac amyloidosis (ATTR-CM), but the prognostic value of quantitative metrics remains incompletely defined. We investigated their prognostic utility and additive value beyond existing staging systems. Methods Retrospective study of patients undergoing technetium-99m-pyrophosphate (PYP) SPECT/CT, including consecutive clinically referred patients (October 2023 to 2024) and trial participants with positive scans from January 2022. Myocardial PYP was quantified using standardized uptake values (SUV mean and SUV max ) and volumetric measures [percent injected dose (%ID), cardiac amyloid activity (CAA)]. Major adverse cardiovascular events (MACEs) comprised heart failure hospitalization or death. Cox and Kaplan–Meier analyses assessed associations; likelihood ratio testing and change in area under the curve (AUC) evaluated the additive prognostic value to existing staging systems. Results Among 43 patients with ATTR-CM, 16 experienced MACE over a median 518 days. AUCs ranged from 0.74 to 0.88 at 3 months and 0.56–0.62 at 12 months. All variables trended toward association with MACE: SUV mean ( P = 0.02), SUV max ( P = 0.03), %ID ( P = 0.06), and CAA ( P = 0.06). After age adjustment, cut-points for SUV max (5.8) and SUV mean (3.5) remained associated with MACE. Adding imaging variables to the National Amyloidosis Centre and Columbia staging systems did not significantly improve prognostic accuracy (Δ χ 2 : 0.40–2.48, P = 0.11–0.53). Interobserver reproducibility was high (intraclass correlation coefficients = 0.89–0.99). Conclusion Quantitative Tc-99m–PYP SPECT/CT metrics were associated with short-term outcomes in ATTR-CM, but did not improve established staging systems. Findings are hypothesis-generating and require validation in larger cohorts.

Malignant glioma is considered invariably recalcitrant, thus necessitating development of new therapeutic approaches. Spontaneously arising canine glioma exhibits important molecular and pathological similarities to malignant pediatric glioma, making it an invaluable model for testing novel therapies. We evaluated safety and activity of RNA lipid particle aggregates (LPAs) designed to provoke cancer immunogenicity in 10 dogs with histologically confirmed glioma. Vaccine manufacturing was feasible in all subjects and generally well tolerated. Median survival time was 123 and 155 days in dogs receiving three (Group A) or four (Group B) vaccines, respectively; this was increased from historical reporting of subjects receiving palliative care. Responding animals had a robust cytokine response following infusions. In animals receiving non-specific RNA-LPAs, there was localization of messenger RNA (mRNA) payloads to the brain tumor microenvironment and a rapid shift in immunologic gene signatures consistent with a viral response. These data demonstrate the ability to induce rapid viremic response in the tumor microenvironment following a single peripherally administered mRNA vaccine. Since RNA-LPAs are amenable to repeat boosts, these formulations may overcome challenges of tumor immunosuppression and therapeutic access and are currently under evaluation in first-in-human trials ( NCT04573140 , NCT06389591 ).

Importance Transthyretin amyloid cardiomyopathy (ATTR-CM) is underdiagnosed despite expanding treatment options. Objective To develop and evaluate an artificial intelligence (AI)–augmented clinical program for ATTR-CM detection. Design, Setting, and Participants This nonrandomized clinical trial involved constructing an AI model, ATTRACTnet, using electrocardiogram waveforms, echocardiographic measurements, demographics, and diagnosis codes for orthopedic manifestations of amyloidosis. A single-system, multisite, single-arm, open-label trial was conducted to evaluate its real-world performance. The model was trained and validated at a large academic referral site for ATTR-CM with external validation at an academic site. The trial was conducted as a single-system, multisite trial. Patients with left ventricular (LV) wall thickness 12 mm or more and an ATTRACTnet score 0.5 or higher were eligible. Exclusions included prior ATTR-CM testing, hypertrophic cardiomyopathy, expected life span less than 1 year, nursing home residence, advanced dementia, or LV wall thickness less than 14 mm explained by uncontrolled hypertension or moderate/severe aortic stenosis. Intervention Eligible patients were notified and offered nuclear scintigraphy testing, monoclonal protein testing, and follow-up care on agreement from the treating physician. Main Outcomes and Measure The primary outcome was a diagnosis of ATTR-CM by consensus criteria. ATTR-CM testing positivity was compared with historical and contemporary controls. Results ATTRACTnet was developed in an internal test set of 799 patients (mean [SD] age, 75.1 [11.1] years; 516 [64.7%] male and 283 [35.3%] female) using 5-fold cross-validation with an additional external test set of 422 patients. It had good discrimination for ATTR-CM detection with an area under the receiver operator characteristic curve of 0.85 (5-fold cross-validation, 0.77-0.85) in the internal set and 0.82 (95% CI, .81-0.83) in the external test set with similar performance in Hispanic, non-Hispanic Black, and non-Hispanic White patients. A total of 1471 patients were identified with positive AI model scores 0.5 or more during the study period, with 256 eligible patients who met study criteria. Of these patients, 50 underwent amyloidosis testing after physician and patient approval; 24 (48%) were diagnosed with ATTR-CM, and 21 (88%) initiated treatment within 3 months. The positivity rate was more than 2.8 times higher than historical controls (15.3%; 95% CI, 13.1%-17.9%; P < .001), with an 18% relative increase in new diagnoses vs the prior year. Conclusions and Relevance AI-augmented screening may improve ATTR-CM detection and identify patients who are missed by usual care. Prospective randomized trials are needed to determine if outcomes are improved. Trial Registration ClinicalTrials.gov Identifier: NCT06469372

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.

Abstract BACKGROUND PCNSL is an aggressive brain tumor accounting for 3% of all CNS malignancies and is associated with poor prognosis. Standard of care treatment includes induction with high-dose methotrexate based chemoimmunotherapy followed by consolidation with autologous stem cell transplant or whole brain radiation. However, more than half of PCNSL patients cannot tolerate this intensive therapeutic intervention. Novel treatments are urgently needed. Toll-like receptor signaling pathway via MyD88/IRAK-4 signalosome is constitutively active in PCNSL secondary to MYD88 L265P mutation and represents an excellent therapeutic target. Emavusertib (CA-4948) is an oral first-in-class small molecule inhibitor of IRAK-4 that demonstrates clinical activity in patients with systemic Non-Hodgkin’s Lymphoma, however it has not been evaluated in the CNS space. HYPOTHESIS: Emavusertib has anti-tumor activity against preclinical PCNSL. METHODS Using multiparameter immunohistochemistry (IHC) and proteomics analysis, IRAK-1, IRAK-4, and NF-κB pathway activation were examined in patient PCNSL tissues as compared to normal controls. Plasma, cerebrospinal fluid, and brain tissue were assessed via UPLC-MS/MS for emavusertib drug concentration following single oral high dose in a murine model. Survival responses in preclinical PCNSL models were measured in response emavusertib treatment, along with in vivo tumor proliferation and downstream biomarker expression by multi-parameter IHC. RESULTS Our data confirm elevated IRAK-1, IRAK-4, and NF-κB signaling in patient PCNSL. We show that emavusertib can achieve therapeutically relevant concentrations in the brain and CSF. Emavusertib impairs tumor cell proliferation in vitro and in vivo, and shows dose-dependent single-agent activity in preclinical PCNSL models. We confirm decreased ERK1/2, MAPK and NF-κB activation, indicative of downstream IRAK-4 inhibition. CONCLUSIONS Our data supports that emavusertib demonstrates anti-tumor activity in the CNS space, warranting further preclinical and clinical evaluation of this agent for the treatment of PCNSL.

Abstract Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P < .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P < .001), as was overall survival (HR, 1.32; P < .001, and HR, 1.45; P < .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.