450 Background: Inactivating genomic alterations (GA) of FANCC gene are associated with genomic instability, DNA cross-linking, and homologous DNA repair deficiency (HRD). FANCC GA are most frequently associated with colon, lung, breast, and prostate cancers (0.5% frequency) with germline FANCC mutations linked to familial breast cancer. FANCC GA have been rarely associated with RT and are not currently linked to any hereditary renal cancer predisposition syndromes. We evaluated the incidence of FANCC GA and other genomic features across cancer types. Methods: 463,546 clinically advanced cancers (CAC) underwent hybrid capture-based comprehensive genomic profiling using the FDA-approved F1CDx assay to detect all classes of GA. MSI status, tumor mutation burden (TMB), gLOH, prediction of germline status, genomic ancestry, and genomic signature were determined with algorithm-based analysis. PD-L1 expression was tested by IHC (Dako 22C3 tumor proportional score; low positive (LP) 1-49%). Results: 1,993 (0.43%) CAC featured FANCC GA. 27 of these FANCC-mutated tumors (20 male, mean age 57) were RT (0.35% of 7,668 RT): 13 clear cell, 3 sarcomatoid, 3 urothelial, 3 chromophobe, 2 squamous cell, 2 medullary renal carcinomas (RCC), and 1 Wilm’s tumor. The primary tumor was sequenced in 9 cases and a metastatic site in 18 (5 lymph node, 4 soft tissue, 3 brain, 2 liver, 1 each lung, adrenal, eye, bone). Only 1 of 25 tested FANCC-mutated RT was MSI-high. The mean TMB was 5.7 mut/Mb while the median TMB was 2.5 mut/Mb, and 4 cases (15%) featured TMB ≥10 mut/Mb. 2 of 4 FANCC-mutated RT that were tested for PD-L1 were LP. The mean gLOH was 7.5%. Genomic ancestry evaluation revealed 21 EUR, 4 AFR, and 2 AMR patients. Genomic signature could be assessed in 5 cases: 4 were MMR deficient. The FANCC mutations included inactivating short variant mutations in 24 cases (10 nonsense, 10 frameshift, 2 non-frame and 2 splice-site mutations) and 3 truncating rearrangements ( FANCC: SUSD3, FANCC: FANCC, FANCC: C20orf24). Interestingly, 14 (52%) of the FANCC-mutated RT were predicted to be germline. Additional GA in the FANCC-mutated RT included VHL, TP53, CDKN2A, ARID1A, PBRM1, TERT, PTEN, and SETD2. Conclusions: Somatic and germline mutations in FANCC occur in an exceedingly small subset of clinically advanced RT but at similar rate to other cancers. RT with inactivated FANCC do not appear to have a different GA landscape from RT with wild-type FANCC. The high frequency of predicted germline status during somatic testing with FANCC alterations suggests the importance of further workup with confirmatory germline testing as it may affect counseling for other family members. Limitations of this study include lack of clinical and therapy data annotation.

172 Background: Lynch syndrome is the most common hereditary syndrome associated with colorectal cancer (CRC). Lynch syndrome-associated CRC is typically characterized by microsatellite instability-high tumors which exhibit favorable response to PD-1 immune checkpoint inhibitors (ICIs). Our aim was to identify clinical and demographic factors that influence overall survival (OS) in Lynch syndrome-associated CRC patients treated with pembrolizumab, a PD-1 ICI. Methods: We designed a multicenter retrospective study using TriNetX, a global database of de-identified electronic health records, to evaluate the impact of multiple covariates on OS in patients with Lynch syndrome and stage IV CRC treated with pembrolizumab. Patients who underwent colectomy were excluded. Using the Cox proportional hazards model, we explored the effect of sex, age at index, marital status, obesity, type 2 diabetes mellitus, chronic kidney disease, nicotine dependence, alcohol use, depression, and metastasis to lung, liver, bone, brain, peritoneum or retroperitoneum. Results: Of the 394 patients diagnosed with both Lynch syndrome and stage IV CRC receiving pembrolizumab, 44.7% were males. Increased mortality risk was observed in males compared to females [HR 1.558, 95% CI 1.085-2.235; p=0.016]. Additionally, peritoneal and retroperitoneal metastases were significantly associated with worse OS [HR 1.822, 95% CI 1.151-2.882; p=0.010]. Age at index, marital status, obesity, type 2 diabetes mellitus, chronic kidney disease, nicotine dependence, alcohol use, depression, and lung, liver, bone or brain metastases were not significantly associated with worse OS. Conclusions: Male sex and presence of peritoneal or retroperitoneal metastases are poor outcome predictors in Lynch-associated stage IV CRC treated with pembrolizumab. The latter adverse prognostic indicators emphasize the need for careful risk stratification when treating Lynch-associated stage IV CRC patients with pembrolizumab and further guide treatment decisions. Effect of several covariates on overall survival (OS) in patients with Lynch syndrome and stage IV colorectal cancer treated with pembrolizumab. Covariate Hazard Ratio Coefficient Standard Error z P > |z| 95% Confidence Interval Male 1.558 0.443 0.184 2.405 0.016 (1.085, 2.235) Age at Index 1.013 0.013 0.007 1.913 0.056 (1.000, 1.027) Overweight and obesity 0.728 -0.317 0.214 -1.479 0.139 (0.478, 1.109) Nicotine dependence 1.476 0.389 0.219 1.772 0.076 (0.960, 2.269) Alcohol use 0.000 -15.887 2330.127 -0.007 0.995 -- Married 0.980 -0.020 0.185 -0.111 0.912 (0.682, 1.407) Type 2 diabetes mellitus 1.444 0.368 0.205 1.789 0.074 (0.966, 2.160) Depression 0.974 -0.026 0.232 -0.113 0.910 (0.618, 1.536) Chronic kidney disease (CKD) 1.291 0.256 0.227 1.125 0.261 (0.827, 2.016) Secondary malignancy of retroperitoneum and peritoneum 1.822 0.600 0.234 2.563 0.010 (1.151, 2.882)

e18118 Background: The incidence of early-onset (EO) head and neck cancers (HNC), defined as diagnosis before age 50 years, is increasing. EO-HNC exhibits a heterogeneous clinical course, and factors influencing overall survival (OS) remain incompletely characterized. We sought to identify clinical and demographic variables associated with OS in patients with EO-HNC. Methods: We conducted a multicenter retrospective cohort study using the TriNetX Research Network, a federated database of de-identified electronic health records. Adults diagnosed with EO-HNC were identified. The association between clinical and demographic covariates and OS was evaluated using Cox proportional hazards regression. Covariates included age at diagnosis, sex, race, primary tumor site, nicotine dependence, alcohol use disorder, obesity, type 2 diabetes mellitus, hypertension, and chronic obstructive pulmonary disease (COPD). Results: A total of 39,358 patients with EO-HNC were identified, of whom 56.9% were male. Factors significantly associated with increased mortality included male sex (HR 1.72; 95% CI, 1.59–1.85; P<0.0001), increasing age at diagnosis (HR 1.03; 95% CI, 1.02–1.03; P<0.0001), primary tumor site at the base of tongue (HR 2.81; 95% CI, 2.00–3.94; P<0.0001) or oropharynx (HR 2.05; 95% CI, 1.38–3.04; P<0.0001), White race (HR 1.09; 95% CI, 1.00–1.19; P=0.04), Black or African American race (HR 1.44; 95% CI, 1.27–1.62; P<0.0001), nicotine dependence (HR 1.29; 95% CI, 1.14–1.45; P<0.0001), alcohol use disorder (HR 1.61; 95% CI, 1.32–1.96; P<0.0001), COPD (HR 1.58; 95% CI, 1.22–2.05; P=0.001), and hypertension (HR 1.21; 95% CI, 1.08–1.36; P=0.001). Primary tumor site at the tonsil was associated with improved survival (HR 0.55; 95% CI, 0.32–0.94; P=0.029). Primary site at the palate or larynx, obesity, type 2 diabetes mellitus, and HPV status were not significantly associated with OS. Conclusions: In this large multicenter cohort of patients with EO-HNC, survival was adversely affected by male sex, increasing age at diagnosis, race, select primary tumor sites, tobacco and alcohol use, and cardiopulmonary comorbidities. Tonsillar primary tumors were associated with improved outcomes likely secondary to impressive response rates to chemoradiation in this often HPV positive cohort. These findings underscore the prognostic heterogeneity of EO-HNC and may aid in risk stratification and patient counseling.

e23570 Background: Soft tissue sarcomas (STS) are rare, and metastatic disease confers a poor prognosis. There are limited treatment options for systemic disease, and standard chemotherapy is the first line for many subtypes. Given the success of ICI (immune checkpoint inhibitors) in many solid tumors, ICI has been investigated in STS as well. This retrospective observational study aimed to investigate the efficacy of ICI in STS. Methods: We queried the Global Collaborative Network, comprising 170 HealthCare Organizations, using the TriNetX research platform, a federated network of de-identified electronic medical records, for identifying patients with soft tissue sarcoma (STS) using ICD10CM as well as ICD-O codes. Population was divided into two cohorts based on receipt of ICI. Propensity score matching (1:1 greedy nearest-neighbor, caliper 0.1) was performed for age, race, gender, and comorbidities. Kaplan–Meier survival analysis and comparative statistics were performed. Using the Cox proportional hazards model, we explored the effect of covariates including sex, age at index, race, marital status, obesity, nicotine dependence, alcohol use. Results: 14,623 STS cases were identified, of which 363 received ICI. Patients who received ICI were older (61.2 ± 16.4 vs 56.1 ± 19.2 years, p< 0.001), predominantly whites (75% vs 50%, p < 0.001); no significant difference in gender (males: 54% vs 49%, p = 0.0785). Prior to PSM, median follow up period was 358.5 days in ICI group and 846 days in non-ICI group. Survival probability at the end of time window was lower in ICI group (10.57% vs 22.56%, p < 0.001). After PSM, the group which received ICI had lower survival probability (11.26% vs 29.31%, p < 0.001), with median OS of 520 days in ICI group compared to 3161 days in non-ICI group. On reviewing the cox proportional hazard models, it was seen that nicotine dependance (HR 1.266 (1.096, 1.462), p = 0.0013), being male (HR 2.977 (2.589, 3.423), p < 0.001), or older age at index (HR 1.148 (1.076, 1.224), p < 0.001) increased the risk of death, while being married (HR 0.877 (0.815, 0.945), p = 0.0005)) decreased the risk of death. Conclusions: Our study aids in providing real-world data regarding the use of ICI in STS. In literature, we have seen no significant difference between ICI and SOC with OS ranging from 6.1 - 17 months with ICI. Even though our study did not show any survival benefit compared to non-ICI cohort, the median OS of ~17 months in ICI group is equivalent to current literature. STS are heterogenous disease, and further studies are required to determine which histologic subtype would benefit most from ICI.

e23560 Background: Soft tissue sarcomas (STS) have historically been treated with surgery, radiation, or chemotherapy. Recent studies and clinical trials have investigated the use of immune checkpoint inhibitors (ICI) either alone or in combination with chemotherapy. Here we present a meta-analysis examining ICI use in STS. Methods: A systemic search with terms encompassing STS and ICI was conducted in PubMed and Embase on January 11, 2026. A total of 1494 records were identified, which were imported into Rayyan, and titles were screened independently by 2 reviewers. 134 records were relevant, and full texts were reviewed. Only studies in which ICI was utilized for STS treatments were included. RevMan was used for analysis, and the Binary Random-Effects (RE) model was used for Pooled Proportions (PP) analyses. Results: ICI cohort had a total of 4455 patients. Using the RE model, the pooled proportions of patients achieving Complete Response (CR) was 1.7% (1.3% - 2.1%, p < 0.001, I^2 0), Partial Response (PR) was 17.7% (15.5-20.0, p < 0.001, I^2 79.057), and Stable Disease (SD) was 43% (39% - 47.1%, p < 0.001, I^2 84.044) while no response was seen in 33.5% patients (28.4% - 38.6%, p < 0.001, I^2 91.06). Overall Response Rate, (not including SD) was estimated to be 23.1% (20.4%-25.8%, p < 0.001). There was substantial heterogeneity across studies (I^2 86.629) for ORR. Current literature shows that using chemotherapy, mainly anthracycline based, has CR < 10%, PR 15-30%, and ORR 20-40%. Conclusions: Pooled data using ICI in sarcoma shows good overall response rates, especially the partial response rates. Current literature shows that using chemotherapy, mainly anthracycline based, has CR < 10%, PR 15-30%, and ORR 20-40%. Our data is very comparable to chemotherapy regimens. While meta-analysis results can be confounded by heterogeneity between studies, results of ongoing clinical studies that may result in near future may help better answer this question.

537 Background: Prognostic genomic assays (GA) have become crucial in the management of early-stage hormone receptor positive breast cancer, particularly in guiding adjuvant chemotherapy decisions. Despite this, GA remain underutilized. This study aimed to identify predictors of GA utilization and associated survival outcomes. Methods: The 2023 NCDB PUF dataset was used to identify patients aged ≥ 18 years with HR positive, HER2 negative breast cancer diagnosed between 2010-2023. Patients with T1-T4, N0-N1 disease who underwent surgical resection were included, while those with T1aN0 stage, M1 disease, unknown GA status, or receipt of BCI alone were excluded. Patients were stratified by the receipt of the GA. Descriptive and multivariable analyses were performed to identify factors associated with GA utilization, and survival was assessed using Kaplan-Meier (KM) analysis. Results: 594,872 patients were included in our study, of whom 63.12% (N=375,506) underwent GA testing. GA utilization increased over time from 52.7% in 2010-2015 period to 68.7% in 2021-2023 (p<0.001). Using multivariable analysis, higher odds of GA testing were seen among Whites vs Blacks (OR 1.13 (1.11-1.16)), those with T2 tumors vs T1 (OR 1.26 95% CI 1.24-1.27), Grade 2 (OR 1.49 (1.47-1.51) or Grade 3 (1.42 (1.39-1.45)) histology vs Grade 1, receiving regional lymph node surgery vs not (OR 2.47 (2.33-2.62)), hormonal therapy vs not (OR 2.39 (2.34-2.43)), radiation vs not (OR 1.32 (1.30-1.34)), and recent year of diagnosis, 2021+ vs 2010-2015 (OR 2.08 (1.99-2.18)). The odds of GA testing were lower for uninsured vs government insured patients (OR 0.86 (0.82-0.91)), those with higher T stages (T3: OR 0.63 (0.61-0.65) and T4: OR 0.26 (0.24-0.30)) vs T1, N1 disease vs N0 (OR 0.73 (0.72-0.74)) and increasing age with the lowest odds among patients aged>80 (OR 0.13 (0.13-0.14)) compared to 18-64 years old. KM analysis showed survival benefit favoring receipt of GA (HR= 0.4 (0.39-0.41), p<0.001). Conclusions: Our study portrays low utilization of GA despite increasing use over time reflecting the impact of the TAILORx and RxPONDER trials. Significant disparities persisted by age, insurance status, race, and tumor characteristics. Older, Black and uninsured patients were substantially less likely to receive testing, despite an associated survival benefit, underscoring the need for more equitable implementation of guideline-recommended GA.

4138 Background: CAGAC is an aggressive malignancy with poor prognosis where chemotherapy and immunotherapy provide a limited benefit. There have been clinical trials investigating the benefit of PARP inhibitors in biliary tract cancers. HRDsig positivity in other types of cancer have shown to predict sensitivity to PARP inhibitors. We explored the genomic characteristics of CAGAC patients according to the HRDsig status using a large real-world genomic dataset. Methods: Comprehensive genomic profiling was performed on 2,423 cases of CAGAC to assess all types of genomic alterations (GA), including base substitutions, short insertions and deletions, copy number changes, rearrangements, and fusions. Microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic ancestry, and trinucleotide signatures were determined from the sequencing data. PD-L1 was determined with the DAKO 22C3 IHC assay. HRDsig status was determined by measuring large scale copy number changes and DNA repair errors. Patients were grouped into HRDsig positive (HRDsig+) and negative (HRDsig-) based on results. Genes with GA ≥5% in either population were included in the analysis. Results: Among 2,423 total cases, 152 (6.3%) were HRDsig+. Between MRDsig+ and MRDsig-, there was no significant difference in gender (female 76.3% vs 69.1%, p = 0.061), age (median 66.5 vs 68.0 yrs; p = 0.065), genomic ancestry (EUR 67.6% vs 63.7%, p = 1.0), MSI-H status (0.0% vs 1.3%, p = 0.468), PD-L1 expression (Low 34.0% vs 23.4%, p = 0.529. High 1.9% vs 5.4%, p = 0.946). Median GA per tumor was the same between groups (median 5 vs 5, p = 0.723), but the proportion of TMB≥10 mut/Mbp were higher in HRDsig+ (12.5% vs 4.7%, p = 0.001). HRDsig+ had more frequent alterations in BRCA1 (9.2% vs 1.4%, p < 0.001), BRCA2 (21.7% vs 1.9%; p < 0.001), PALB2 (11.2% vs 0.4%; p < 0.001), NF1 (9.9% vs 4.4%; p = 0.018), PIK3R1 (5.9% vs 2.5%; p = 0.05), and PTEN (11.8% vs 5.3%; p = 0.015). HRDsig- had more frequent alterations in ERBB2 (5.9% vs 19.0%, p < 0.001), KRAS (5.9% vs 14.9%, p = 0.007), and MDM2 (3.3% vs 9.4%, p = 0.024). Conclusions: HRDsig positivity comprised approximately 6% of all CAGAC cases. HRDsig+ were associated with a higher proportion of mutations related to homologous recombination repair (HRR) genes and mTOR pathway, whereas HRDsig- demonstrated a higher proportion of common driver mutations such as ERBB2 and KRAS. Notably, there were cases with discordant HRDsig and HRR mutation status, which may be attributed to factors such as epigenetic alterations or mono-allelic alterations. These cases may represent the role of HRDsig complementing HRR mutation status and potentially have clinical implications in predicting response to PARP inhibitors.

BACKGROUND:Sitosterolemia is a rare inherited condition caused by elevated levels of plant sterols in the plasma, characterized by mutations in ABCG5 and ABCG8 genes. A scarce occurrence in this condition are hematological abnormalities such as hemolytic anemia, stomatocytosis, and macrothrombocytopenia. We conducted a meta-analysis and systematic review to answer these questions regarding patients who have hemolytic anemia and ABCG8 mutation. METHODS:13 reports were shortlisted for the final analysis (Observational studies-6, case series-4, case reports-3). Descriptive statistics were utilized to study the patient characteristics. RESULTS:From the 13 reports that we found in available literature, we identified 19 cases of ABCG8 mutation and anemia. From the random-effects proportions model, the chance of this event occurring among patients with sitosterolemia was 6.8% [0.068, 95% Confidence Interval (CI) 0.016-0.120, P=0.010] (I2 24.68%) (14/145). Thrombocytopenia and stomatocytosis were frequently reported. Splenomegaly and xanthomas were other common associations. CONCLUSIONS:To the best of our knowledge, we provide the first report of the prevalence of anemia, specifically in patients with sitosterolemia caused by a mutation in the ABCG8 gene. At 6.8%, this is an extremely rare occurrence in an already infrequent disease.

Background/Objectives: This study investigates genomic alterations (GA) between NPM1-mutated (NPM1mut) and wild-type (NPM1wt) acute myeloid leukemia (AML), aiming to better understand the AML genomic profile. NPM1mut AML represents a distinct clinical AML subtype with high relapse rates despite initial responsiveness to chemotherapy. Methods: A total of 4206 AML cases from 2019 to 2024 were analyzed using the FoundationOne Heme assay, incorporating comprehensive DNA and RNA sequencing. Patients were stratified into NPM1mut and NPM1wt cohorts, and genomic differences were systematically compared between the two groups. Results: Among 4206 cases, 633 (15.1%) featured NPM1 GA, with over 99% exhibiting short variant mutations. NPM1mut AML was more common in females (53.4% vs. 41.5%) and associated with a slightly higher median age (62 vs. 60 years). GA was more frequent in NPM1mut AML compared to the NPM1wt and included DNMT3A (39.2% vs. 12.6%; p < 0.0001), PTPN11 (18.3% vs. 7.5%; p < 0.0001), FLT3 (54.5% vs. 14.7%; p < 0.0001), IDH1 (16.1% vs. 5.6%; p < 0.0001), IDH2 (19.0% vs. 9.0%; p < 0.0001), TET2 (23.4% vs. 13.5%; p < 0.0001), and WT1 (12.5% vs. 9.4%; p = 0.02). GA was more frequent in NPM1wt AML and included ASXL1 (17.1% vs. 3.6%; p 0.0001), BCOR (7.5% vs. 1.6%; p < 0.0001), KMT2A (14.7% vs. 0.2%; p < 0.0001), RUNX1 (22.5% vs. 1.9%; p 0.0001), STAG2 (6.9% vs. 1.6%; p < 0.0001) and TP53 (19.1% vs. 4.1%; p < 0.0001). Conclusions: Mutations linked to therapy targets in AML, such as (FLT3 and IDH1/2), PTPN11, and DNMT3A (both associated with inferior outcomes), are more commonly observed in NPM1mut AML, whereas KMT2A, TP53, and myelodysplastic-related mutations are more commonly observed in NPM1wt AML.

6528 Background: NPM1 GA characterize a clinically important subset of AML cases which relapse in more than 50% of treated patients despite being generally sensitive to conventional chemotherapy regimens. In AML, the interactions between GA in NPM1 , KMT2A and menin protein have been linked to leukemogenesis and represent new potential targets for anti-tumor therapies. Methods: 4,206 cases of AML underwent comprehensive genomic profiling from 2019 through 2024, using the FoundationOne Heme combined hybrid capture based DNA and RNA sequencing assay. All classes of relevant GA were evaluated. The tumor mutation burden (TMB), homologous recombination deficiency signature (HRDsig) and microsatellite Stability (MSS) status were determined from the sequenced data. Results: 633 (15.1%) of the 4,206 AML featured NPM1 GA (NPM1mut). Short variant mutations were found in >99% of the NPM1mut AML with the W288fs*12 frameshift base substitution accounting for 92.4% of cases. An NPM1 - MLF1 fusion was identified in 1.3% of NPM1mut cases. The NPM1mut+ were more frequently associated with female patients (53.4% vs 41.5%; p<.0001) and had a slightly higher median age compared to the NPM1 wild type (NPM1wt) AML patients (62yrs vs 60yrs; p<.0001). Majority of patients (>60%) were from European decent. There were greater NPM1 GA in patients with European (77.1% vs 68.5%; p<.0001) and lower with African ancestry (9.2% vs 10.2%; p<.0001). MSI High (0% in both groups) status, HRDsig+ (0—0.1%) and elevated TMB (median < 1 mutation/Mb) were extremely uncommon in both groups. GA more frequent in NPM1mut AML compared to the NPM1wt AML cohort included DNMT3A (39.2% vs 12.6%; p<.0001), FLT3 (54.5% vs 14.7%; p<.0001) , IDH1 (16.1% vs 5.6%; p<.0001), IDH2 (19.0% vs 9.0%; p<.0001), TET2 (23.4% vs 13.5%; p<.0001) and WT1 (12.5% vs 9.4% p=.02). GA more frequent in NPM1wt AML included ASXL1 (17.1% vs 3.6%; p,.0001), BCOR (7.5% vs 1.6%; p<.0001), KMT2A (14.7% vs 0.2%; p<.0001), RUNX1 (22.5% vs 1.9%; p-,.0001), STAG2 (6.9% vs 1.6%; p<.0001) and TP53 (19.1% vs 4.1%; p<.0001). Conclusions: The development of menin inhibitors has recently identified GA in NPM1 as a promising target of therapy for AML patients. Other therapy targets in AML such as FLT3 and IDH1/2 are more frequently identified in NPM1mut than NPM1wt AML, while KMT2A is more frequently identified in NPM1wt AML. This genomic landscape study reveals significant differences in important GA associated with AML in NPM1mut and NPM1wt cases which may enrich our understanding of the molecular profile in AML and identify additional targets for therapy. Pathogenic genomic alterations in NPM1mut and NPM1wt AML. NPM1wt AML (n=3573) NPM1mut AML (n=633) P-value ASXL1 17.1% 3.6% <.0001 CEBPA 6.4% 8.2% NS DNMT3A 12.6% 39.2% <.0001 FLT3 14.7% 54.5% <.0001 IDH1 5.6% 16.1% <.0001 IDH2 9.4% 19.0% <.0001 KMT2A 14.7% 0.2% <.0001 RUNX1 22.5% 1.9% <.0001 TET2 13.5% 23.4% <.0001 TP53 19.1% 4.1% <.0001

Background: Acute erythroid leukemia (AEL) is considered a rare and aggressive subtype of acute myeloid leukemia (AML). There is some controversy surrounding the exact nature of AEL as a distinct clinicopathologic entity. Whilst the ICC classification system includes AEL under the broader category of AML with TP53 mutations, the WHO 2022 classification uses the term to describe cases of pure erythroid leukemia which requires ≥80% erythroid predominance in the bone marrow with ≥30% proerythroblasts. Owing to its relative rarity, accounting for only 3-5% of all AML cases, available information regarding optimal treatment and prognosis is limited. Although survival outcomes for TP53 mutant AML are still extremely poor, cumulative evidence has suggested a better efficacy for use of a hypomethylating agent with venetoclax in TP53 mutant AML. We therefore conducted a retrospective cohort study to determine survival outcomes of AEL compared to AML and further studied survival outcomes in AEL patients treated with traditional 7+3 induction regimen compared to use of a hypomethylating agent with venetoclax. Methods: We utilized databases from the TriNetXtmglobal federated health research network which included 107 different healthcare organizations. By utilizing ICD-10 and ICD oncology codes, patients with acute myeloid leukemia and acute erythroid leukemia were identified as separate cohorts. Separate cohorts were identified for acute erythroid leukemia cases based on time to initiation of either idarubicin or daunorubicin with cytarabine, or azacitidine or decitabine with venetoclax within 4 weeks of the index diagnosis event. Propensity score matching (PSM) was conducted, matching cohorts based on age, gender, race and prior exposure to antineoplastic agents. Primary outcome measure of interest was all-cause mortality, and Kaplan-Meier survival analysis was conducted excluding patients with primary outcome prior to index diagnosis event. Relapsed acute erythroid leukemia was a secondary outcome measure, and Pearson's chi-squared test was employed to analyze measures of association. Results: A total of 93,667 AML patients and 1,581 AEL patients were identified. 1,581 patients in each cohort were 1:1 PSM matched. Baseline characteristics including age, gender, race, and exposure to antineoplastic agents were well balanced in both cohorts. Kaplan-Meier analysis on estimates of overall survival probability at 1-year and 5-years was 72.4% and 54.5% in the AML cohort vs 69.7% and 54.6% in the AEL cohort respectively (log-rank test p=0.093 for 1-year analysis and p=0.73 for 5-year analysis). A total of 126 patients with AEL who received induction 7+3 regimen and 92 patients with AEL who received HMA + venetoclax were identified. 48 patients in each cohort were 1:1 PSM matched. Baseline characteristics including age, gender, race, and exposure to antineoplastic agents were well balanced in both cohorts. Kaplan-Meier analysis on estimates of overall survival at 1-year predicted a median overall survival of 343 days in the AEL who received 7+3 cohort versus 140 days in the AEL who received HMA + venetoclax cohort, and a survival probability of 49.5% versus 22.8% respectively at 1-year (log-rank p-value 0.012) and 28.6% versus 0% at 5-years (log-rank p-value=0.0008). An equal number of patients relapsed in both treatment cohorts (n=10), and no risk difference was subsequently noted. Conclusion: AEL represents a rare and aggressive subtype of AML with poorly defined outcomes. These patients may have better survival outcomes with upfront 7+3 chemotherapy induction regimens compared to upfront use of hypomethylating agents with venetoclax, and argues in favor of considering this rare subtype as a distinct clinicopathologic entity. Further prospective studies are warranted to explore differences in treatment outcomes.

Background: Sickle cell disease (SCD) is hereditary blood disorder leading to anemia, vaco-occlusive crises, organ damage. Its treatment remains challenging. There are various reports of utilization of Erythropoietin Stimulating Agents (ESAs) in sickle cell patients along with hydroxyurea showing some benefit in decreasing sickle cell crisis.[1-3] Here, using global research network dataset, we evaluate outcomes of using ESAs in SCD. Methods: Trinetx, a global federated research network that provides a dataset of electronic medical records from different healthcare organizations (HCOs), was utilized. Initial query was made to isolate patients with age >18 years, who had SCD without crisis or sickle cell/thalassemia disease or sickle cell/Hb-C disease (ICD 10 codes D57.1, D57.2, D57.4, D57.80) and Hemoglobin levels between 7 and 10 gm/dl. The population was divided into two cohorts based on receipt of ESAs (EPO, Epoietin alfa, Darbepoetin alfa). Propensity Score matching (PSM) was carried to match age, sex, race, chronic heart failure, chronic lung disease, neoplasms, chronic kidney disease stages 4 and 5, use of hydroxyurea and crizanlizumab. Outcomes of all-cause mortality (ACM), sickle cell crisis, ischemic stroke, cardiac ischemia and other arterio-venous thrombosis were evaluated. Results: 19,143 patients with SCD were identified, of whom 9.14% (n=1750) patients received EPO. The patients who received EPO were older (49 ± 18.2 vs 32.2 ± 17.4 years, p<0.0001), with more males receiving EPO (10.01% vs 8.81%, p=0.019). Use of hydroxyurea was found to be more in EPO group (37% (n=629) vs 16% (n=1568), p<0.0001). The median follow- up period was 887.5 days in EPO group and 1078 days in non-EPO group. All-cause mortality was high for patients receiving EPO (31.94% (544) vs 8.94% (1499), p<0.0001, OR = 4.78 (4.26, 5.36) with Hazard ratio 4.21 (3.82, 4.65; log-rank test = p<0.0001)). Sickle cell crisis risk was less in patients receiving EPO (14.86% (129) vs 36.34% (3521), p<0.001, OR=0.31 (0.25,0.37) with HR 0.34 (0.28,0.41)). The risk of developing stroke (11.56% vs 6.52%, p<0.0001), cardiac ischemia (17.91% vs 5.15%, p<0.0001), and other arterio-venous thrombosis (19.62% vs 9.36%, p<0.0001) was high in EPO group. After PSM, the all-cause mortality was still high in EPO group (29.22% vs 20.21%, p<0.0001, OR=1.63 (1.33,1.99), HR=1.3 (1.09,1.55)) with no significant difference in sickle cell crisis (20.25% vs 19.19%, p=0.6607, OR=1.07 (0.79,1.44)). The risk of cardiac ischemia (15.03% vs 9.16%, p<0.0001), and other arterio-venous thrombosis (18.86% vs 11.58%, p<0.001) remained higher in EPO group, while there was no significant difference in risk of stroke (10.71% vs 8.59%, p=0.1233). Conclusion: This real-world data shows that ESAs use does increase the utilization of hydroxyurea, but its significance in improving survival and sickle cell crisis still needs to be evaluated with prognostic studies. The study also highlights potential risks of arterio-venous thrombosis with the use of ESAs. Reference:Obeagu EI. Maximizing longevity: erythropoietin's impact on sickle cell anaemia survival rates. Ann Med Surg (Lond). 2024 Jan 24;86(3):1570-1574. doi: 10.1097/MS9.0000000000001763. PMID: 38463100; PMCID: PMC10923353.Santosh Saraf, Robert Molokie, Michel Gowhari, Johara Hassan, Victor R. Gordeuk; Clinical Efficacy and Safety of Erythroid Stimulating Agents in Sickle Cell Disease. Blood2012; 120 (21): 3218. doi:Little JA, McGowan VR, Kato GJ, Partovi KS, Feld JJ, Maric I, Martyr S, Taylor JG 6th, Machado RF, Heller T, Castro O, Gladwin MT. Combination erythropoietin-hydroxyurea therapy in sickle cell disease: experience from the National Institutes of Health and a literature review. Haematologica. 2006 Aug;91(8):1076-83. PMID: 176885048; PMCID: PMC3522485.

Background: Targeted regimens incorporating selective inhibitor of BCL-2 like venetoclax and Bruton Tyrosine Kinase inhibitors (BTKi) like ibrutinib have redefined first-line therapy for B-cell chronic lymphocytic leukemia (CLL), demonstrating high rates of undetectable measurable residual disease and durable progression-free survival in randomized trials. Fixed-duration ibrutinib–venetoclax has shown efficacy across risk groups compared to ibrutinib alone, but both regimens carry distinct toxicity profiles, such as neutropenia, infections, and cardiovascular events. Trials often under-represent patients with advanced age, significant comorbidities, or impaired renal function, limiting generalizability to the broader CLL population. We present real-world data for comparative effectiveness and safety of this regimen in broader clinical practice. Methods: TrinetX, a global federated research network that provides a dataset of electronic medical records from different healthcare organizations (HCOs), was utilized. Initial query was made to isolate patients with treatment naive B-CLL excluding ones with TP53 mutation or IGHV gene rearrangements. The population was further divided into two groups, those who received BTKi monotherapy (ibrutinib, zanubrutinib, acalabrutinib) and those who received fixed duration BTKi and venetoclax combination (IV). Further, propensity score matching (PSM) was carried out for age, sex, race, ethnicity, and co-morbidities like IHD, heart failure, diabetes, hypertensive diseases, hyperlipidemia, peripheral vascular disease, atherosclerosis, overweight and obesity, CKD stage 3 and higher, ESRD, cerebrovascular diseases, emphysema, COPD, fibrosis and cirrhosis of liver along with WBC, Hb, platelets and ANC before starting treatment. The primary outcome of interest was overall survival (OS). Secondary outcomes of interest were rate of hospital and ICU admissions, any infection, tumor lysis syndrome (TLS) and cardiovascular outcomes (MACE, Atrial fibrillation/flutter, AV blocks and other arrhythmias). Outcomes were measured from day 1 after administration of BTKi or IV combination. Analysis methods included Kaplan-Meier survival estimates using log-rank test, as well as Cox regression for hazard ratio (HR), measures of association, and number of instances, with T-test statistics assessing differences between cohorts. Results: After 1:1 propensity score matching, a total of 326 patients were included (163 in each cohort). The median follow-up duration was 730 days for the BTKi monotherapy group and 606 days for the BTKi plus venetoclax (IV) group. Baseline characteristics were well balanced between cohorts. After PSM, both groups had no significant difference in survival probability (90.6% in the BTKi group and 86.3% in the IV group). The Kaplan Meier curves were not separated, with a log-rank test showing p=​​0.167 and HR = 0.61 (0.289-1.248, 95% CI; p = 0.109). Hospital and ICU admissions occurred in 20.2% of BTKi group and 25.2% of IV group, with a mean number of admissions of 1.06 vs 0.47, respectively (p = 0.227). Tumor lysis syndrome was observed in 6.1% of patients in both groups (risk ratio = 1.00; 95% CI: 0.43–2.34). Cardiovascular events (including MACE, AV block, atrial fibrillation/flutter and other arrhythmias) occurred in 20.2% of BTKi group and 23.9% of IV group (odds ratio [OR] = 0.81; 95% CI: 0.48–1.36; p = 0.423). Infection-related complications were slightly more common in the IV group (28.2%) compared to BTKi (24.5%) (OR = 1.21; 95% CI: 0.74–1.99; p = 0.449). Conclusion: This real-world study suggests that BTKi monotherapy is non-inferior to fixed-duration BTKi and venetoclax combination therapy in terms of 2-year OS for treatment-naive B-CLL patients without TP53 mutations or IGHV gene rearrangement. We noted no statistically significant difference in the safety profiles of BTKi monotherapy and fixed-duration IV combination therapy.

Introduction: Sickle cell disease (SCD) is an inherited disorder affecting the beta-globin gene encoding the beta-globin subunit of a hemoglobin molecule. This leads to crescent shape or ‘sickling’ of the red blood cells. Triggers for ‘sickling’ like dehydration, infection, stress, or hypoxemia - can precipitate vaso-occlusion and result in sickle cell crisis due to blockage of blood flow by sickle cells to essentially any organ of the body. This often leads to frequent admissions for a ‘pain crisis’, acute chest syndrome, stroke, renal dysfunction. A previous retrospective audit at our institution underscored inpatient care distinction between patients on the hematology service as compared to general medicine service . To address these gaps in care, we created a standardized Adult Sickle Cell admission order set at our institution aimed at improving care for sickle cell patients. Methods: We performed a retrospective review of the usage of our ‘Adult sickle cell crisis admission’ order set between June 2024 and July 2025 at SUNY Upstate University Hospital. Data for usage was provided by our IT team using SlicerDicer after IRB waiver. Clinical data was extracted from EPIC EMR. The order set was created through a collaborative effort by hematologists at our institution and included medications like a reminder to reorder home hydroxyurea if appropriate, daily folic acid tablets, adjunct pain medications and options for opioid pain regimens, options for hypotonic and regular intravenous (IV) fluids to order on admission, labs on admission, daily labs some of which were pre-selected, quick access to order bowel regimens, deep vein thrombosis (DVT) prophylaxis and incentive spirometry. Time to adequate pain control was calculated (defined as time in hours from admission to a patient-reported pain score of 3 or lower on a numerical rating scale out of 10). Z score for proportions was used to calculate p values comparing our results to the prior institution audit (n=1404 patients) Results: The ‘Adult sickle cell crisis admission’ order set was used 25 times in this time period. The mean age was 32 years; 52% were male and 100% were of African American race. The median Charlson Deyo comorbidity index was 1 (vs 0 in the pre-intervention study). Mean length of hospital stay was 7 days (range 1 - 25 days), 4% of patients required ICU level of care (vs 3.8% in the pre-intervention study, p=0.96) and 3 other patients required ICU monitoring for ketamine infusion per institute policy. Time to adequate pain control was 69.2 hours. 76% of patients were placed on patient-controlled analgesia (PCA) on admission (vs 22% in the pre-intervention study, p=<0.0001). 100% of patients with home hydroxyurea had it resumed on admission, 100% of patients had a bowel regimen (vs 79.1% in the pre-intervention study, p=0.01), and 100% had a form of DVT prophylaxis ordered on admission (vs 73.9%% in the pre-intervention study, p=0.003). Moreover, 92% had incentive spirometry ordered on admission. 40% of patients had a pain service consultation during admission (vs 20.2% in the pre-intervention study, p=0.015), and 4% developed a new DVT/PE during admission. 96% had IV fluids ordered on admission (vs 94.8% in the pre-intervention study, p=0.787) with a mean rate of fluids of 113 ml/hour. The mean hemoglobin was 8.8 mg/dl on admission and 9.0 mg/dl on discharge. Conclusion: Our single institute study demonstrates improvement in sickle cell crisis quality of care measures especially with higher admission order metrics such as DVT prophylaxis, bowel regimen, IV fluids and usage of PCA for adequate pain control. There was no change in requirement of escalation to ICU level fo care and an increase in the mean duration on PCA post intervention. This single institution experience underscores the potential for distinction of sickle cell care between different providers and provides a standardized plan of care to optimize sickle cell inpatient care.1. Bou Zerdan M, Niforatos S, Ashok Kumar P, et al. Distinguishing the variances in patient care between hematologists and hospitalists for individuals with sickle cell disease hospitalized due to Vaso-occlusive crisis. Blood. 2023;142(Supplement 1):3675–3675.

Background: High-risk myelodysplastic syndromes (HR-MDS) carry a poor prognosis, with median overall survival under three years and post-hypomethylating agent (HMA) failure survival as low as 4 to 6 months. HMAs have been the standard of care but yield only ~50% initial response and limited long-term benefit. Oral decitabine/cedazuridine (DEC-C) was FDA-approved in 2020 as the first oral HMA for MDS and CMML and offer a similar safety and efficacy to IV/SC decitabine with trends toward improved treatment persistence and acute myeloid leukemia (AML)-free survival in real-world datasets. Meanwhile, venetoclax combined with HMAs in HR-MDS has shown promising response rates with improved potential for transplantation in responders, although substantial myelosuppression is common with the dual agent therapy. We conducted a retrospective cohort study to determine survival outcomes and progression to acute myeloid leukemia in HR-MDS patients treated upfront with oral DEC-C compared to use of intravenous HMA with venetoclax (VEN/HMA) in HR-MDS patients. Methods: We utilized the TriNetXtmglobal federated health research network which included 149 different healthcare organizations. By utilizing ICD-10 and ICD oncology codes, patients with HR-MDS were identified and separated into two cohorts based on time to initiation of either oral DEC-C, or azacitidine or decitabine in combination with venetoclax within 4 weeks of the index diagnosis event. Propensity score matching (PSM) was conducted, matching cohorts based on age, gender, race and prior exposure to antineoplastic agents. Primary outcome measure of interest was overall survival (OS), and Kaplan-Meier survival analysis was conducted excluding patients with primary outcome prior to the index diagnosis event. Progression to AML was a secondary outcomes measure, and Pearson's chi-squared test was additionally employed to analyze measures of association. An analysis using Cox-proportional hazards model for progression to AML was performed with covariates including age, sex, race, and Charlson comorbidity index including acute myocardial infarction, heart failure, personal history of malignant neoplasm, cerebral infarction, dementia, chronic pulmonary disease, liver disease, diabetes and chronic kidney disease. Results: A total of 125 patients with HR-MDS who were treated upfront with DEC-C and 351 such patients who received VEN/HMA were identified. 116 patients in each cohort were matched 1:1 based on PSM. Baseline characteristics including age, gender and race were well balanced in the matched cohorts. Kaplan-Meier estimates of survival at 5-years predicted a median OS of 695 days in the upfront DEC-C treated HR-MDS cohort compared to 421 days in the upfront VEN/HMA treated HR-MDS cohort, corresponding to OS probability at 5-years of 37.2% and 16% respectively (log-rank test p=0.0323). Kaplan-Meier estimates of risk of progression to AML at 5-years predicted a risk of progression of 614 days in the DEC-C group versus 214 days in the VEN/HMA group, with overall risk of progression at 5-years of 44.9% and 9% respectively (log-rank test p=0.032). In addition, overall risk of progression at 5-years estimated by hazards ratio (HR)was 0.57 with 95% CI 0.4 – 0.82 (p=0.0038) in favor of DEC-C treatment group. Risk of progression to AML by Cox-proportional hazards model showed statistically significant benefit associated with younger age and upfront treatment with DEC-C, HR of 0.98 (95% CI 0.96 – 0.99, p = 0.031) and 0.38 (95% CI 0.17 – 0.87, p = 0.021) respectively. Conclusion: Our matched cohort analysis of front-line use of DEC-C was associated with better OS and lower risk of progression to AML compared to VEN/HMA in HR-MDS patients. Further prospective studies are warranted to confirm such benefits associated with this new oral agent in the treatment of HR-MDS patients.

Immune checkpoint inhibitors (ICI) have become integral to treatment of non-small cell lung cancer (NSCLC). However, reliable biomarkers predictive of immunotherapy efficacy are limited. Here, we introduce HistoTME, a novel weakly supervised deep learning approach to infer the tumor microenvironment (TME) composition directly from histopathology images of NSCLC patients. We show that HistoTME accurately predicts the expression of 30 distinct cell type-specific molecular signatures directly from whole slide images, achieving an average Pearson correlation of 0.5 with the ground truth on independent tumor cohorts. Furthermore, we find that HistoTME-predicted microenvironment signatures and their underlying interactions improve prognostication of lung cancer patients receiving immunotherapy, achieving an AUROC of 0.75[95% CI: 0.61-0.88] for predicting treatment responses following first-line ICI treatment, utilizing an external clinical cohort of 652 patients. Collectively, HistoTME presents an effective approach for interrogating the TME and predicting ICI response, complementing PD-L1 expression, and bringing us closer to personalized immuno-oncology.

7066 Background: Three CAR-T cell therapies i.e. axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel are currently approved for relapsed refractory DLBCL after 2 or more prior lines of treatment. Landmark trials have shown promising efficacy however, a notable concern with CAR-T therapy is the potential development of secondary primary malignancies. Methods: A retrospective study was performed using TriNetX, a global research de-identified database with data from 145 health care organisations as of January 2025. ICD-10 codes were used for associated diagnosis and medications. The database was queried to identify RR-DLBCL patients who had received any of axi-cel, tisa-cel or liso-cel. These treatments were set as the index event for outcome analysis. Demographics and prevalence of comorbidities were extracted. Outcome analysis queried for several hematological and solid tumor malignancies. The Measure of Association Analysis was used to calculate Odds Ratio. Results: 1842 adult patients with RR-DLBCL received one of the 3 CAR-T cell treatments as listed above and 12,431 patients with RR-DLBCL did not receive any of the 3 treatments. There were 1:1 propensity score matched adjusting for age, race, sex and tobacco use. Final number for both groups was 1842. For both cohorts, 1367 (73.8%) were white, 1055 were male (57%). The cohort had a mean follow up of 497 days, median follow up of 331.5 days. The CAR-T group had higher rates of MDS (3.9% vs 0.8%, p=<0.001) and AML (3.2% vs 1.2%, p=<0.001) in our database review of the US population. It did not show higher rates of other reported SPMs like Mature T/NK cell lymphoma, Hodgkin's lymphoma, multiple myeloma or solid tumours like lung, breast, prostate primary or malignant melanoma. Data on other SPMs is shown in Table 1. Conclusions: In our retrospective study of real-world population, RR-DLBCL patients who received CAR-T cell therapy with any of axi-cel, tisa-cel or liso-cel showed higher rates of MDS and AML compared to propensity matched patients with RR-DLBCL who did not receive CAR-T cell therapy while rates of other reported SPMs were not significantly different. Frequency of SPMs in CAR-T receiving and no CAR-T receiving patients with RR-DLBCL. SPM Received CAR-T cohort (%) Did not receive CAR-T cohort (%) Odds Ratio p-value MDS 3.9 0.8 4.852 (2.767-8.507) <0.001 AML 3.2 1.2 2.668 (1.624-4.382) <0.001 Mature T/NK cell lymphoma 0.7 1.5 0.466 (0.238-0.909) 0.022 Hodgkin's lymphoma 0.9 1.9 0.469 (0.257-0.854) 0.011 Follicular lymphoma 3.8 3.6 1.055 (0.721-1.545) 0.781 Mantle cell lymphoma 1.0 0.5 1.792 (0.825-3.893) 0.135 Multiple Myeloma 1.4 2.4 0.566 (0.341-0.938) 0.025 Primary Lung site 0.7 0.5 1.292 (0.565-2.954) 0.543 Primary Breast site 0.5 0.7 0.815 (0.351-1.892) 0.634 Prostate cancer 0.5 0.6 0.902 (0.382-2.129) 0.814

Background: CAR-T cell therapy has transformed the treatment landscape of diffuse large B-cell lymphoma (DLBCL). Autologous stem cell transplant (ASCT) has long been a cornerstone in DLBCL management. However, the benefit of consolidative ASCT after CAR-T remains unclear. Methods: Using TriNetX, adults (≥18 years) with DLBCL treated with tisacel, lisocel or axicel were identified. Cohort 1 was CAR-T alone; Cohort 2 was CAR-T followed by ASCT. Propensity score matching yielded 560 patients per cohort. Outcomes included overall survival (OS), remission, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), ICU admission, and hospitalization. Results: Median follow-up was 430 vs. 633 days (CAR-T vs. CAR-T→ASCT). OS risk was 30.4% vs. 36.0%, risk difference (RD) –5.7% (95% CI –11.2 to –0.2; p=0.044), median OS 1824 vs. 1484 days (HR 1.10; 95% CI 0.90–1.36; p=0.34). Remission rates were similar (RD –0.9%, 95% CI –3.2 to 1.5; p=0.47). MDS incidence was higher with ASCT (RD –3.0%, 95% CI –5.3 to –0.7; p=0.01), while AML was similar (p=0.18). ICU admission RD was 3.0% (95% CI –1.6 to 7.5; p=0.20) but HR 1.47 (95% CI 1.05–2.07; p=0.025). Hospitalization RD was 7.7% (95% CI –0.1 to 15.4; p=0.072) but HR 1.99 (95% CI 1.05–3.80; p=0.020). Conclusions: ASCT after CAR-T in DLBCL did not improve OS and was associated with increased MDS incidence and higher ICU and hospitalization hazards. Further clinical trials should be designed and studied.