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Background. Study of myeloid neoplasms (MN) has been rapidly transformed by genome characterization. Gene mutations have been reported to influence disease phenotype and risk of disease progression, and the evaluation of mutational status can provide valuable insights to improve the decision-making process. In this international study, we evaluated the clinical impact of mutational screening in patients with CMML, which is characterized by significant clinical and genomic heterogeneity, including a substantial proportion of patients with poor outcomes and unmet needs. Currently, only limited molecular information has been incorporated into CMML classification and prognostication. Methods. We retrospectively collected 3182 CMML patients. We used MOSAIC, an AI-based framework for multimodal analysis in rare cancers (PMID: 38875514) to develop innovative, molecular-based tools for classification and prognostication. An independent validation of the results on 516 prospectively collected patients was performed. Results. Bayesian Networs and Hierarchical Dirichlet Processes were used to identify genomic associations and define a CMML molecular classification. We identified 11 clusters with distinct clinical and genomic features, including splicing machinery, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures (i.e., AML-like and TP53 mutations). Up to 15% of patients showed clear genomic overlap with other MN. Importantly, extensive multi-color flow cytometry on T lymphocytes, NK and myeloid cells (BD FACSymphony A5 Cell Analyzer) revealed specific immunologic and inflammation signatures associated with molecular subgroups. We then integrated molecular and clinical information to build an international CMML Prognostic Scoring System (iCPSS). We assessed the performance of different statistical and AI-based methods; L1-penalized Cox Model resulted as the best performing method. Selected features included hematological parameters (WBC, Hb, PLT and marrow blasts), cytogenetic abnormalities, and mutations in 10 genes (ASXL1, DNMT3A, EZH2, NRAS, RUNX1, SETBP1, STAG2, TET2, TP53, U2AF1). By Bayesian thresholds optimization, we identified 5 risk classes (i.e., very-low, low, intermediate, high and very-high) with median overall survival (OS) ranging from 99 to 9 months (P<.001), and median leukemia-free survival (LFS) ranging from 210 to 18 months (P<.001). iCPSS provided better patient discrimination across all clinical endpoints compared to currently available prognostic tools, with a Concordance Index (CI) for OS of 0.75 versus 0.62-0.64, respectively. Notably, compared to available scoring systems, up to 40% of patients were reassigned to higher or lower risk classes by the iCPSS. External validation on an independent prospective cohort confirmed that the performance of iCPSS is superior to existing prognostic models (CI for OS 0.71 vs 0.54-0.61, respectively) To demonstrate the clinical utility of iCPSS, we focused on 753 patients who underwent allogeneic stem cell transplantation (HSCT). In multivariable analysis, iCPSS stratified the probability of OS post-HSCT (P<.001) and identified groups of patients with different probabilities of disease relapse, ranging from 9% to 62% (P<.001). We employed a clinical- and genomic-based decision support system (PMID: 38723212) to determine the optimal timing of HSCT. Preliminary analyses indicated that higher-risk patients according to iCPSS (i.e., intermediate, high, and very high) benefit from an immediate HSCT strategy. Lower-risk patients (i.e., very low and low) had life expectancy maximized with delayed HSCT. Modeling decision analysis using iCPSS compared to conventional scores, resulted in a change in transplantation policy for a significant proportion of patients (up to 25%). Conclusion. Molecular information significantly improves the classification of CMML patients, providing a basis for refining diagnostic boundaries with other MN and for a more rational inclusion of patients in clinical trials. The iCPSS demonstrated superior performance over currently available scoring systems and improved HSCT decision making process.

Introduction Patients (pts) with relapsed/refractory (R/R) myelodysplastic syndromes (MDS) have a poor prognosis and, until recently, lacked therapeutic options. Ivosidenib (IVO) is an oral, targeted, small-molecule inhibitor of mIDH1. In October 2023, IVO was granted FDA approval for the treatment of adult pts with mIDH1 R/R MDS on the basis of results from the pivotal AG120-C-001 MDS substudy (NCT02074839); IVO showed an acceptable safety profile and induced durable remissions, with a high rate (38.9%) of complete remissions (CR) per International Working Group (IWG) 2006 criteria (DiNardo et al. Blood Adv 2024; bloodadvances.2023012302.). Response criteria evolve to better reflect clinical benefit in specific pt populations and reduce interobserver variability. The updated IWG 2023 criteria for higher-risk MDS lowered the hemoglobin threshold for CR, added response categories for pts with <5% blasts or limited count recovery, and eliminated the marrow CR (mCR) category. Herein we analyze responses, transfusion independence (TI), and survival outcomes of pts treated with IVO according to IWG 2023 criteria. In addition, responses assessed per IWG 2023 and IWG 2006 criteria are compared. Methods Pts with mIDH1 R/R MDS who had received prior SOC therapy were eligible. Oral IVO 500 mg was administered daily on days 1-28 of 28-day cycles. Responses were assessed per IWG 2023 criteria, and a composite CR (CRc) category was included in the analysis, which comprises all CR categories: CR + CR equivalent (CRe) + CR with limited count recovery (CRL) + CR with partial hematologic recovery (CRh). Overall response rate (ORR) was defined as CR + mCR + partial remission (PR) per IWG 2006 criteria, and as CRc + PR + hematologic improvement (HI) per IWG 2023 criteria. For TI analysis, non-CRc was defined as HI + PR + no response (NR)/not evaluable + progressive disease. TI was defined as requiring no transfusion for ≥56 days. Results In total, 19 pts were enrolled (median age: 73 yr; prior hypomethylating therapy: 78.9%) and data from 18 efficacy-evaluable pts were analyzed. CR + PR rate (primary endpoint) per IWG 2006 was 38.9%, with all 7 (38.9%) responders having CR. CRc + PR rate per IWG 2023 was 66.7% (n=12), with all responders having CRc, including 5 (27.8%) pts with CR, 3 (16.7%) with CRe, and 4 (22.2%) with CRL (CR unilineage [CRLuni], n=2 [11.1%]; CR bilineage [CRLbi], n=2 [11.1%]); no pt had CRh or PR. ORR was 83.3% per IWG 2006, with 7 (38.9%) pts having CR and 8 (44.4%) mCR; 4 (22.2%) pts with mCR had HI. Per IWG 2023 criteria, the ORR was 72.2%, with 12 (66.7%) pts having CRc and 1 (5.6%) HI with neutrophil response. The 8 mCR per IWG 2006 criteria were reclassified as 1 CR, 4 CRL (2 CRLuni and 2 CRLbi), 1 HI, and 2 NR per IWG 2023. Median time to CRc was 1.58 mo. Median duration of CRc was not reached and Kaplan-Meier (KM) estimates at 3, 6, and 12 mo were 90.9%, 81.8%, and 68.2%, respectively. Five (CRc group n=4; non-CRc group n=1) of 7 (71.4%) and 3 (CRc, n=1; non-CRc, n=2) of 4 pts requiring red blood cell (RBC) and platelet transfusion at baseline, respectively, had TI. Median time to any (RBC/platelet) TI was 2.64 and 2.43 mo for pts with CRc and non-CRc, respectively. Moreover, 10 of 12 (83.3%) pts with CRc and 3 of 6 (50%) with non-CRc had or maintained TI during the study. Median duration of TI was not reached and KM estimates at 3 and 6 mo were 90.0% and 65.6%, respectively, for pts with CRc and 100% and 66.7% for non-CRc. Median event-free survival (EFS) was not reached for pts with CRc (n=12) or NR (n=5), and KM estimates at 1 yr were 68.2% and 53.3%, respectively. Median overall survival (OS) was not reached for pts with CRc and was 16.5 mo for pts with NR. For pts with CRc, OS KM estimates at 1, 3, and 5 yr were 90.9%, 51.1%, and 51.1%, respectively. For pts with NR, OS KM estimates were 75% at 1 yr and not estimable at 3 and 5 yr. For the pt with HI, the EFS estimate at 1 yr was 100% and OS estimates were 100% at 1, 3, and 5 yr. Conclusions IVO resulted in a high ORR (72.2%) according to IWG 2023 criteria, including a 66.7% CRc rate, despite the removal of the mCR category. Of 8 mCR per IWG 2006 criteria, 5 (62.5%) were reclassified as CRc per IWG 2023 criteria. By eliminating mCR and assessing response in a high-risk population with <5% blasts, IWG 2023 criteria accurately capture the clinical benefit of IVO in R/R MDS. While comparison of survival outcomes between IWG 2006 and IWG 2023 is limited by the small sample size, a similar trend with response-dependent EFS and OS outcomes was observed.

Background and Significance: Systemic mastocytosis (SM) is a rare heterogeneous disease characterized by the aberrant accumulation of neoplastic mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of KIT. Advanced SM (AdvSM) is a life-threatening form of SM and includes three subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Despite improvement in disease control with approval of tyrosine kinase inhibitors (TKIs), there is still unmet need for improved tolerability and efficacy in AdvSM treatments. Bezuclastinib, an oral and selective type 1 TKI that potently inhibits KIT D816V, is being studied in patients diagnosed with AdvSM in the Apex study (NCT04996875). Results from the Part 1 dose optimization portion of Apex were presented previously. Part 1 randomized 32 patients 1:1:1:1 to receive bezuclastinib at 50, 100, or 200 mg BID or 400 mg QD. Initial results from the Part 1 dose optimization portion of the Apex trial in patients with AdvSM demonstrated encouraging safety profile and signs of clinical activity, as well as deep reductions across biomarkers of MC burden including bone marrow MC burden, serum tryptase levels, and KIT D816V variant allele fraction (VAF). In addition, 94%, 93%, and 100% of patients demonstrated ≥50% reduction in serum tryptase, KIT D816V VAF, and bone marrow MC burden, respectively. Exposure achieved with 100 mg BID of bezuclastinib original formulation resulted in optimal efficacy and safety outcomes. 150 mg QD of an optimized formulation is expected to deliver bezuclastinib exposures consistent with the 100 mg BID of the original formulation. Part 2 is further evaluating the efficacy and safety of bezuclastinib in patients with AdvSM at the selected Part 2 dose of 150mg QD of the optimized formulation. Study Design and Methods: Apex is a multicenter, Phase 2 open-label study of bezuclastinib in patients with AdvSM as defined per the WHO criteria. Enrollment includes previously treated and treatment-naïve patients. Part 2 is enrolling approximately 65 patients including up to 15 patients without measurable mIWG C-findings. The Part 2 expansion portion of the Apex study is designed to evaluate the efficacy and safety of bezuclastinib in patients with AdvSM, including ASM, SM-AHN, or MCL. Key eligibility criteria include measurable disease (centrally adjudicated) according to modified IWG-MRT-ECNM criteria and clinically acceptable laboratory values including platelet count ≥50,000/µL. The primary efficacy endpoint of Part 2 is overall response rate (ORR = complete response [CR] + complete remission with partial hematologic recovery [CRh] + partial response [PR] + clinical improvement [CI]) per mIWG-MRT-ECNM criteria according to mIWG-MRT-ECNM response criteria and will be confirmed by a Central Response Review Committee. Secondary endpoints include further characterization of safety and tolerability, pure pathologic response, biomarker response (including changes in bone marrow MC burden, serum tryptase level, and KIT D816V mutational burden), duration of response, time to response, progression-free survival, and overall survival (OS). Apex Part 2 is actively enrolling. Study sites are enrolling in North America, Asia-Pacific, and Europe. In addition, a high-risk SM-AHN sub-study assessing the safety and feasibility of the combination of bezuclastinib 150 mg QD and azacitidine may enroll up to 20 patients who are currently receiving or indicated for azacitidine and have biopsy-proven SM with an associated high- or very high-risk myeloid neoplasm. Patients with SM-AHN from Part 1 or Part 2 who have demonstrated AHN progression may enroll in an additional rollover cohort to receive bezuclastinib with concomitant azacitidine or hydroxyurea.

Introduction The pathogenic role of somatic non-coding (nc) single nucleotide variants (SNVs) is underexplored in multiple myeloma (MM) and additional characterization of these regions has the potential to provide significant new insights into disease progression. To investigate the role of ncSNVs and their relationship with MM pathogenesis, we have characterized a novel series of WGS from 294 cases of MGUS, SMM, and MM using computational tools optimized to identify functional driver SNVs in these regions. We hypothesize the ncSNVs that co-localize to sites of super-enhancers (SEs) active in plasma cells (PC) are sites of high functional impact SNVs and these mutations lead to the dysregulated expression of genes that should be silent at the terminally differentiated stage of PCs, providing a selective advantage that shapes the fitness of the MM genomic landscape. Methods We analyzed 294 high-coverage matched tumor/normal pairs (80x tumor and 40x normal) derived from 21 MGUS, 86 SMM, 167 NDMM and 40 RRMM. In addition to previously sequenced samples, newly sequenced patients were obtained from NYU Langone Health, Memorial Sloan Kettering Cancer Center, University of Alabama at Birmingham and University of Miami following IRB-approved informed consent. DNA was extracted from CD138+ purified bone marrow plasma cells using standard approaches. We used the MGP1000 (https://github.com/pblaney/mgp1000) to process sequencing data which employs a union-consensus mechanism for determining the final set of variants. We collected enhancer elements (E/SEs) active in GC B-cells, ABC-DLBCL and GBC-DLBCL (Bal, et al. Nature, 2022) and PC specific E/SEs (Loven, et al. Cell 2013). FunSeq2 was used to score ncSNVs. GRAM was used to predict how variants alter TF binding and gene expression in a subset of 6 cases with paired WGS in our series and will expand this analysis on a validation set of 263 NDMM and 93 RRMM cases from University-Hospital Heidelberg enrolled in the GMMG-HD6 clinical trial. Results We identified 1,952,232 high-quality SNVs with 18,199 (0.93%) accumulating in 280 focal sites we termed “mutationally enriched regions” or MERs. To discern SNVs in MERs with the highest potential for imparting a selective advantage, we clustered mutations based on the density of FunSeq2 impact scores which uses reference data contexts on sequence conservation, modification of transcription factor (TF) binding, and gene linkage to regulatory elements and network hubs from pan-cancer studies. We show that MERs are enriched for ncSNVs with high impact scores (mean=2.57) compared to random similarly-sized regions of the genome (Fisher's exact test P<9.7e-12, OR=10.10 [3.88-37.40]). The high impact ncSNVs (hi-ncSNVs) in MERs (n=220) account for 8.09% of all hi-ncSNVs and are present in 46.3% of cases (136/294) with some patients having up to 7. The proportion of cases carrying a MER hi-ncSNVs was similar across disease stages (MGUS=42.9%, SMM=46.5%, MM=40.7%, and RR=47.5%). Analysis of the VAF of MER hi-ncSNVs shows a minor shift towards more clonal versus subclonal mutations (53.6% vs 46.4% VAF>=0.25) suggesting some high impact mutations are acquired in the GC but additional hi-ncSNV are acquired later in PC development, providing evidence that hi-ncSNVs accumulate in MERs throughout disease progression. We mapped these hi-ncSNVs to associated genes then intersected the loci with E/SEs active in GCBs and PCs to determine their functional context. This approach identified 12 genes affected by hi-ncSNVs including the previously identified nc-drivers NEAT1, MIR142, ZCCHC7, and IGLL5 as well as the PC differentiation genes IRF8, BACH2, proliferation genes RHOH, SPRED2, known coding MM drivers CCND1, ZFP36L1, and chr1q genes BTG2 and CROCC. We predicted the effect of ncSNVs on expression through modulation of TF binding at this set of putative nc drivers in MM and identified a trend towards increase in expression of SPRED2, CCND1, NEAT1, and IGLL5 compared to non-mutated cases (P=0.089). We will present data on the validation of this set of genes on a larger set of data derived from the Heidelberg group. Conclusions We identified a set of 12 putative nc driver genes in MM that modify expression and have the potential to significantly alter the pathogenesis of MM by providing a selective survival advantage. We will present the impact of these by clinical stage and on outcome.

Abstract Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.

Objective To define the natural history, patterns of recurrence and treatment modalities for local prostate cancer (PCa) recurrence following radical prostatectomy (RP) and radiation therapy (RT), and to investigate factors that could predict metastasis‐free survival (MFS) in this unique patient population. Methods We queried a prospectively maintained PCa registry to identify men developing in‐field recurrence (IFR) following RP and RT from 2008 to 2021 at a single institution. IFR was defined as biopsy‐proven recurrent PCa or the presence of persistent positron emission tomography‐avid lesions in the prior radiation field without evidence of metastasis. Cox regression was conducted to determine predictors of MFS. Kaplan–Meier methods were used to calculate MFS, cancer‐specific survival (CSS) and overall survival (OS) for patients in three primary therapy categories: cryoablation, androgen deprivation therapy (ADT) alone, and surveillance. Results Of 4575 patients from our registry, 108 (2.3%) with IFR were identified. The median (interquartile range [IQR]) time to IFR from salvage treatment was 78 (50–126) months. A total of 29 patients (26%) were managed with cryoablation, 23 (21%) with ADT, and 28 (25%) with surveillance. The median (IQR) follow‐up was 76 (48–100) months. There were no statistically significant differences in MFS ( P = 0.67) or OS ( P = 0.07) among the three primary treatment cohorts. Patients treated with ADT or cryoablation had longer CSS compared to patients managed with surveillance ( P = 0.047). Conclusions We found that IFR may present years after completion of primary treatment for PCa. While curative management strategies may be attempted, local and distant metastatic recurrence is common and often requires systemic therapy.

Objective: Lateral condyle fractures are the second most common pediatric elbow fracture after supracondylar humeral fractures. Early complications are frequent which can lead to development of long-term problems. Current literature has evaluated short-term outcomes, but few studies have investigated long-term outcomes into adulthood. Our hypothesis is that the majority of pediatric patients with a lateral condyle fracture will have minimal complications and few surgeries as they age. Methods: A population-based database was used to identify patients who sustained a lateral condyle fracture before the age of 18 between 1966 and 2012. Electronic medical records from all treatment centers in the county were reviewed for clinical and radiographic data. Analysis was performed to determine incidence and long term outcomes based on fracture type and treatment. Results: From 1966 to 2012, 227 pediatric lateral condyle fractures were identified. One hundred seventy-seven fractures (78%) had at least 10 year clinical follow up. Incidence was found to be 13.97 per 100,000. We identified 80 (45%) Weiss type 1, 61 (34%) type 2, and 37 (21%) type 3 fractures. The overall complication rate was 17%, of which 47% were identified >10 years from injury. There was no significant difference in complication rates based on fracture type (P = 0.18) or treatment type (P = 0.55). The most common complication was malunion (n = 15), followed by fishtail deformity (n = 4), stiffness (n = 3), lateral epicondylitis (n = 3), nonunion (n = 2), osteoarthritis (n = 2), and tardy ulnar nerve palsy (n = 1). Five patients underwent revision surgery for nonunion, cubitus valgus, malunion with loose bodies, capitellar osteochondral dessicans with malalignment, and ulnar nerve palsy. Conclusions: This population-based study estimated the overall incidence of pediatric lateral condyle fractures to be 14 per 100,000. Displaced fractures had a higher incidence than undisplaced fractures. Complications beyond 10 years are rare, but the need for future revision surgery is possible, therefore, proper patient and family education is necessary at the time of injury. This is the largest study with the longest follow-up for pediatric lateral condyle fractures. Complications were rare but resulted in a 17% complication rate and a 3% reoperation rate at a minimum. Level of Evidence: Level III.

SummaryTo assess the relevance of co‐occurring somatic mutations in TP53‐mutated myeloid neoplasms with ≥10% blasts, we pooled 325 individuals from 10 centres. We focused on comparing three published somatic co‐alteration signatures comprising (1) nine MDS‐related genes (‘ICC‐MDSR’), (2) ICC‐MDSR + additional secondary mutations‐related genes (‘Tazi signature’) and (3) EPI6 (comprising six genes). Outcomes examined were 24‐month overall survival (OS24) and front‐line complete response (CR1). The median age was 69 years with 77% receiving front‐line hypomethylating agents (HMA). All three signatures ICC‐MDSR (p = 0.009), Tazi signature (p = 0.001) and EPI6 (p = 0.025) predicted inferior CR1. In the low‐intensity (HMA) subgroup, only Tazi signature (p = 0.026) predicted inferior CR1. In OS24 analysis of the HMA‐treated subgroup (N = 200), only Tazi signature was adverse (hazard ratio, HR = 1.6 [1.1–2.2]; p = 0.011). However, a forward stepwise multivariable age‐adjusted Cox model including all three signatures picked EPI6 as the sole significant adverse predictor in the entire cohort (p = 0.0001) as well as within the HMA‐treated subgroup (p = 0.0071). These data confirm the value of testing co‐occurring somatic alterations even within a high‐grade TP53‐mutated myeloid neoplasm cohort.

Background: There is limited data on the safety and efficacy of ventricular tachycardia (VT) ablation in patients with chronic kidney disease (CKD). We examined the outcomes of patients with CKD undergoing VT ablation in a nationally representative cohort of patients. Methods: The National Inpatient Sample Database (NIS) was analyzed from 2018 to 2021 to identify patients ≥18 years old with VT undergoing ablation. Patients with atrial fibrillation, atrial flutter, supraventricular tachycardia, or pre-excitation syndrome were excluded. Patients were divided into those with CKD and without CKD. A multivariable logistic regression model was utilized to assess the association of CKD with in-hospital mortality and outcomes after adjusting for confounders. Results: Our cohort included 1608 VT ablation procedures, of which 428 (27%) were performed on CKD patients. Mean age was 63 (±13) years, 318 (19%) were female, and 1194 (74%) were White. 1475 (92%) of the procedures were done at an urban teaching hospital, and 1240 (77%) at a private non-profit hospital. On multivariable analysis, CKD was associated with significantly higher odds of death (adjusted odds ration [aOR]: 3.43; 95% confidence interval [CI]: 1.79-6.5; p=0.0002), acute decompensated heart failure (aOR: 3.1; 95% CI 2.24-4.56; p<.0001), bleeding (aOR: 1.53; 95% CI1.02-2.28; p<.03), and acute kidney injury (aOR: 4.49; 95% CI3.42-5.9; p<.0001). There was no difference in the odds of acute myocardial infarction, stroke, cardiogenic shock, vasopressor use, mechanical ventilation, and pericardial tamponade or pericardial procedures Figure . Conclusion: Patients with CKD undergoing VT ablation have an increased risk of mortality and adverse in-hospital outcomes when compared to patients without CKD. These hypothesis-generating findings need validation in future prospective studies for optimal pre-procedural risk stratification.

AbstractObjectiveNeck metastases are a poor prognostic factor in olfactory neuroblastoma (ONB). Pathologic dural invasion (pathDI) may increase the risk of neck metastases due to invasion of dural lymphatics. We aim to evaluate the prognostic value of pathDI in predicting rates of neck metastases and recurrence using a large, multicenter database of ONB patients.Data sourcesRetrospective review of a prospective, multicenter database of electronic health records of all patients who presented with ONB between 2005 and 2021 at nine tertiary academic care centers within North America.Review methodsClinicopathologic features including modified Kadish staging systems, margin status, treatment modalities, Hyams grading, follow‐up time, and survival.ResultsOf 258 ONB patients, 189 patients met the inclusion criteria. The 10‐year neck recurrence‐free survival (neck‐RFS) rates were 85.7% (75.6‒97.3) and 61.8% (47.9‒79.8) for patients without and with pathDI, respectively (p = 0.018). Time‐to‐event multivariable regression analysis found pathDI to have an odds ratios of 9.7 (95% confidence interval [CI] 1.2–80.4, p = 0.04) for neck‐RFS and 9.5 for RFS at any site (95% CI 1.1–83.3, p = 0.04).ConclusionIn multivariable analysis, the presence of pathDI appears to be the strongest predictor of neck recurrence and recurrence at any site. Future studies exploring the benefit of elective neck dissection or radiation for patients with pathDI may impact disease management.