Citations

Abstract Exposure to asbestos is the primary cause of mesothelioma, however the processes underpinning its initiation and evolutionary trajectory remain elusive. To address this knowledge gap, we conducted whole exome sequencing and phylogenetic analysis of 277 mesotheliomas. Using multidimensional Dirichlet process clustering we inferred phylogenies, uncovering mutation order dominated by early 13q,1p, 8p, 6q and 22q somatic copy number alterations. Mesotheliomas exhibit a spectrum of genomic intra-tumor heterogeneity spanning linear (L) to highly branched (B) tree topologies, quantifiable by the Weighted Shannon Entropy (WSE). Somatic copy number alterations emerge earlier than single nucleotide variants (SNVs), and at a much faster relative rate in L-mesotheliomas. BAP1 is the only positively selected driver in L-mesotheliomas, whereas, B-mesotheliomas harbor multiple positively selected drivers and an aggressive phenotype, including a bias of loss of RPL5, and MTAP deletion linked to breakpoint enriched with long interspersed nuclear elements. L-trees had lower WSE, but greater T-cell inflammation and tertiary lymphoid structures, despite having a lower neoantigen burden. WSE is higher in larger volume, immunologically cold mesotheliomas, and is associated with shorter survival. In summary, progressive genomic heterogeneity is a defining feature of more aggressive mesothelioma yet illuminates opportunities for precision therapeutic intervention.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from both B and T cell lineages (B-ALL and T-ALL). Current therapy exploits ALL cells’ low expression of asparagine synthetase (ASNS) by using L-asparaginase, a bacterial enzyme that depletes circulating asparagine. However, resistance can emerge through induction of ASNS, mediated in part by the amino acid stress sensor GCN2. In this study, we addressed the efficacy of L-asparaginase in combination with genetic or pharmacological inhibition of GCN2 and the ASNS inhibitor ASX-173. Using a Kras G12D -driven mouse model of T-ALL, we found that GCN2 is dispensable for leukemogenesis. However, genetic inactivation or pharmacologic inhibition of GCN2 sensitized ALL cells to asparagine depletion, correlating with impaired ASNS induction. While GCN2 targeting enhanced sensitivity to asparagine depletion, a subset of Gcn2 –/– T-ALL cells retained high ASNS expression and remained resistant to L-asparaginase. Likewise, some human T-ALL cells with elevated ASNS levels were refractory to GCN2 inhibition even under asparagine-depleted conditions. When combined with L-asparaginase, ASX-173 effectively eliminated ASNS hi leukemic cells in vitro and in vivo. These findings suggest that direct targeting of ASNS provides therapeutic benefit in leukemias that express high levels of ASNS and are resistant to GCN2 inhibition under asparagine-depleted conditions.

LBA5 Background: Available 2L therapies offer limited clinical benefit in mPDAC with reported mPFS of 3–4 mo and mOS of 6–7 mo. Aberrant RAS pathway activation is the key driver of PDAC, with oncogenic RAS mutations (mut) identified in >90% of cases, most commonly at codon G12. Daraxonrasib is an oral, RAS(ON) multi-selective, tri-complex inhibitor of the active, GTP-bound state of mutant and wild type RAS. Methods: RASolute 302 (NCT06625320) is a global, randomized, open-label, Ph 3 study in pts with 2L mPDAC and ECOG PS 0-1. Pts were randomized 1:1 to receive daraxonrasib 300 mg PO QD or investigator’s choice of SOC cytotoxic chemo. Dual primary endpoints were OS and PFS by BICR in the RAS G12 mutant (RAS G12) population. Key secondary endpoints included OS and PFS by BICR in the overall population, ORR by BICR in RAS G12 and overall populations. Results: 248 pts were randomized to daraxonrasib and 252 to chemo. Baseline characteristics were balanced between arms. At data cutoff (Feb 10, 2026; mFU: 8.5 mo), all primary and key secondary endpoints were met. Statistically significant, clinically meaningful improvements in OS and PFS were observed with daraxonrasib vs chemo in the RAS G12 and overall populations (Table). Gr ≥3 TRAEs occurred in 43.6% of pts receiving daraxonrasib vs 57.5% receiving chemo. The most common (≥10%) Gr ≥3 TRAEs were rash (13.7%) and stomatitis (12.0%) for daraxonrasib; neutrophil decrease (18.2%) and anemia (16.4%) for chemo. TRSAEs occurred in 10.8% of pts receiving daraxonrasib vs 18.7% receiving chemo. Discontinuation due to TRAEs occurred in 1.2% of pts for daraxonrasib vs 11.2% for chemo. Median/mean daraxonrasib dose intensity was 93.1%/84.7%. Conclusions: Daraxonrasib demonstrated unprecedented improvements in OS and PFS vs chemo in pts with 2L mPDAC with or without an identified tumor RAS mut. Daraxonrasib was generally well tolerated, with a manageable safety profile and with no new safety signals. Results support daraxonrasib as the new SOC for 2L mPDAC. Clinical trial information: NCT06625320 . RAS G12 Overall b Daraxonrasibn=228 Chemo n=231 Daraxonrasib n=248 Chemo n=252 OS Median; mos(95% CI) 13.2(10.0–NE) 6.6(5.4–8.2) 13.2(10.0–NE) 6.7(5.8–8.0) HR(95% CI)P-value 0.40(0.30-0.54)<0.0001 0.40(0.30-0.53)<0.0001 PFS a Median; mos(95% CI) 7.3(6.3–8.1) 3.5(2.9–3.8) 7.2(5.7–7.5) 3.6(2.9–4.2) HR(95% CI)P-value 0.45(0.34-0.59)<0.0001 0.49(0.38-0.64)<0.0001 ORR a %(95% CI) 33.2(27.0–39.9) 11.8(7.8–16.8) 31.6(25.8–38.0) 11.2(7.5–15.9) a By BICR. b RAS G12, G13 or Q61 mut or no RAS mut identified.

Ziftomenib - a potent, selective, oral menin inhibitor - is approved as monotherapy for adults with relapsed/refractory (R/R) NPM1-mutated acute myeloid leukemia (NPM1-m AML). The KOMET-007 phase 1 trial investigated clinical activity and tolerability of ziftomenib in combination with standard therapies for R/R and newly diagnosed AML. Here, we report outcomes of adults with R/R NPM1-m AML treated with ziftomenib plus venetoclax/azacitidine. In phase 1a, patients received ziftomenib 200, 400, or 600 mg once daily with standard doses of venetoclax/azacitidine. In phase 1b, ziftomenib 600 mg was selected for expansion. Sixty-seven patients were treated (27 phase 1a; 40 phase 1b). Median age was 66 years, and 55% were men. Median number of prior therapies was 1 (range 1-8); 55% received prior venetoclax and 22% had prior transplantation. Most common (≥20%) grade ≥3 treatment-emergent adverse events were leukopenia (34%), thrombocytopenia (28%), febrile neutropenia and neutropenia (25% each). Six patients developed QTc prolongation (1 ziftomenib-related; grade 1), and 2 experienced differentiation syndrome (grade 3); all events were successfully managed. In patients receiving ziftomenib 600 mg, composite complete remission (CRc) rate was 46% (22/48), with 67% (12/18) achieving central measurable residual disease (MRD) negativity (&lt;0.01% threshold). In venetoclax-naïve and -exposed patients, CRc rates were 70% (16/23) and 24% (6/25), with MRD-negativity rates of 75% (9/12) and 50% (3/6), respectively. Median duration of response was 8.6 months, and median overall survival was not reached. The combination of ziftomenib 600 mg with venetoclax/azacitidine was well tolerated with deep and durable clinical activity in R/R NPM1-m AML. This trial was registered at www.ClinicalTrials.gov as #NCT05735184.

Abstract Background Sepsis is a life-threatening condition in which delayed recognition and treatment are associated with increased mortality. While predictive models such as Epic’s Early Detection of Sepsis Model (ESM) were developed to support early intervention, their real-world impact after integration into clinical workflows remains difficult to evaluate. Objectives To evaluate the real-world impact of ESM integrated into clinical workflow on clinical outcomes, antibiotic use, and harm-benefit tradeoffs. Methods We conducted a quasi-experimental study in a single healthcare system using encounter-level data from inpatient settings. Inpatient mortality, prolonged hospitalization, antibiotic use, and sepsis prevalence were compared between the pre-implementation period (3 June 2023 to 20 August 2024) and the online period (21 August 2024 to 26 December 2024) when the model became visible to clinicians. We also applied a counterfactual framework using models trained on pre-implementation data to estimate expected outcomes without ESM and to quantify harms related to overtreatment and delayed treatment. Results Among 101,138 encounters, 86,884 occurred during the pre-implementation period and 14,254 during the online period. In unadjusted analyses, the online period had lower inpatient mortality, prolonged hospitalization, antibiotic use, and sepsis prevalence (all p≤0.002). In the counterfactual analyses, observed outcomes were lower than expected without ESM for mortality (1.21% vs 1.82%; p<0.001), prolonged hospitalization (5.56% vs 7.95%; p<0.001), and antibiotic use (43.52% vs 47.04%; p<0.001). False positive harm (37.72% vs 41.68%; p<0.001) was also lower than expected. Conclusions Integration of ESM into clinical workflow was associated with improved patient outcomes, reduced antibiotic use, and decreased harm from overtreatment, without evidence of increased harm from delayed treatment, supporting a positive net clinical benefit and the safety and effectiveness of ESM under Software as a Medical Device principles.

This case report describes a 65-year-old man who experienced complete remission of cavin-4 immunoglobulin G (IgG) rippling muscle disease after receiving rituximab therapy.

Objective We aim to identify risk factors to enable stratification of patients' susceptibility to inflammatory arthritis immune‐related adverse events (IA‐irAEs). This retrospective study mainly examines whether preexisting osteoarthritis (OA) increases the likelihood of de novo IA‐irAEs. Methods The prevalence of OA among immune checkpoint inhibitor (ICI)–treated patients who developed IA‐irAE, those who developed other types of irAEs but not IA (non‐IA irAEs), and those who did not develop any irAEs (non‐irAEs) were compared. Electronic medical records were reviewed to extract demographic, clinical, and laboratory data. Group comparisons and logistic regression analyses were performed. Results A total of 181 de novo IA‐irAE patients, 140 non‐IA irAE patients, and 170 non‐irAE patients were included. The prevalence of OA was significantly higher in the IA‐irAE group (69%) than in the non‐IA irAE group (48%) and the non‐irAE group (48%) (both P < 0.001). The IA‐irAE group demonstrated a higher frequency of multisite OA, with more predominant hand involvement (62%) than the non‐IA irAE with OA group (13%) and the non‐irAE with OA group (13%) (both P < 0.001). A family history of autoimmune disease (AID) (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.02–4.05), preexisting OA (OR 2.88, 95% CI 1.85–4.52), and melanoma (OR 2.63, 95% CI 1.56–4.47) were identified as risk factors for the development of IA‐irAE. Conclusion OA was more prevalent among ICI‐treated patients developing IA‐irAE than those who were not. Hand OA was the most common OA pattern in IA‐irAE patients. Preexisting OA, melanoma, and a family history of AID were associated with IA‐irAE.