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e18605 Background: Patients with myelofibrosis (MF), especially those with marked leukocytosis, face increased risk for thrombotic complications such as pulmonary embolism (PE) and venous thromboembolism (VTE). Hydroxyurea (HU) is often used to control blood counts. However, evidence for HU reducing thrombotic events in MF is limited, and contemporary real-world data on its impact in MF populations with significant leukocytosis remain sparse. Methods: We conducted a retrospective cohort study using the TriNetX research network. Adult patients with MF and leukocytosis (white blood cell count ≥25×10⁹/L) were identified. Patients with prior allogeneic hematopoietic stem cell transplantation were excluded. HU-exposed patients were compared with non-exposed patients using 1:1 propensity score matching. Matching criteria included age, sex, race, comorbidities, and baseline laboratory values when available. The study included 3,590 patients (1,795 per cohort). Primary outcomes were time to PE and VTE at 1, 3, and 5 years. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Results: In the propensity-matched cohort, HU exposure was not associated with a statistically significant reduction in thrombotic events. For PE, hazard ratios were numerically higher in the HU-exposed group at 1 year (1.5% vs 1.0%; HR 1.40, 95% CI 0.76–2.56; p=0.278) and 3 years (2.2% vs 1.8%; HR 1.29, 95% CI 0.80–2.08; p=0.289), with a modest increase observed at 5 years (2.8% vs 1.9%; HR 1.57, 95% CI 1.01–2.45; p=0.04). For VTE, no statistically significant differences were observed between HU-exposed and non-exposed patients at any time point (1 year: HR 0.95, 95% CI 0.63–1.44; p=0.821; 3 years: HR 0.97, 95% CI 0.69–1.36; p=0.85; 5 years: HR 1.14, 95% CI 0.84–1.57; p=0.40). Overall, PE and VTE event rates remained low and comparable between cohorts. Conclusions: In this large real-world cohort of patients with myelofibrosis and significant leukocytosis, hydroxyurea exposure was not associated with a statistically significant reduction in thrombotic events, including PE or VTE, over short- or long-term follow-up. Thrombotic event rates were low and generally comparable between hydroxyurea-exposed and non-exposed patients, with no consistent pattern suggesting a protective effect of cytoreductive therapy. Although a modest increase in PE risk was observed at 5 years, this finding was isolated and lacked a consistent temporal pattern, limiting its clinical interpretability. These findings suggest that the role of hydroxyurea in modifying thrombotic risk among MF patients with leukocytosis remains uncertain and highlight the need for individualized treatment decisions and further studies to better define its impact on thrombotic outcomes in this population.

e18602 Background: Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of hematologic malignancies but is frequently complicated by cytokine release syndrome (CRS) and immune-mediated neurotoxicity (NS). As CAR-T programs expand, population-level projections of treatment-related toxicities are essential for program planning and risk mitigation, yet remain poorly characterized. Methods: We performed a cohort-based forecasting analysis using pooled incidence rates of CRS and NS derived from published meta-analyses of CAR-T clinical trials. Expected numbers of toxicity events were projected for hypothetical cohorts of 100, 500, and 1,000 CAR-T–treated patients. Uncertainty was quantified using binomial 95% confidence intervals. Disease-specific projections were generated by applying stratified pooled toxicity rates for hematologic malignancies and solid tumors. Results: For a projected cohort of 1,000 CAR-T–treated patients, forecasts estimated approximately 770 patients would experience CRS of any grade, 290 would develop grade ≥3 CRS, 400 would experience NS of any grade, and 280 would develop grade ≥3 NS. Toxicity counts increased proportionally with cohort size and demonstrated predictable uncertainty bounds. When stratified by disease type, hematologic malignancies exhibited substantially higher toxicity burdens than solid tumors across all endpoints. At a cohort size of 1,000 patients, hematologic malignancies were associated with markedly higher rates of both CRS and severe neurotoxicity, whereas solid tumors demonstrated consistently lower toxicity burdens. Conclusions: Using pooled clinical trial data, this forecasting model provides quantitative estimates of CAR-T–associated toxicity burdens at the population level. Severe CRS and neurotoxicity remain common and scale predictably with program size, particularly in hematologic malignancies. These findings offer a pragmatic framework for anticipating resource utilization, toxicity management needs, and safety planning as CAR-T therapy continues to expand.

e18597 Background: TP53 mutations ( TP53 m) are uncommon in chronic-phase (CP) Philadelphia (Ph) chromosome–negative myeloproliferative neoplasms (MPN) but are increasingly reported in myelofibrosis (MF) and accelerated/blast phase (AP/BP). Their distribution, allelic configuration, and associated clinical outcomes have not been systematically synthesized. Methods: A PRISMA-guided search of EMBASE and PubMed (1974-July 1, 2025) identified cohort studies reporting adult Ph–negative MPNs with molecularly confirmed TP53 m. Case reports were excluded; Conference abstracts were included if cohort-level data were available. Extracted variables included demographics, MPN subtype, disease phase, TP53 allelic status (per International Consensus Classification), variant allele frequency (VAF), allogeneic hematopoietic cell transplantation (allo-HCT), median overall survival (mOS), and leukemic transformation. Given heterogeneity and lack of comparators, pooled proportions with (95% CI) were generated for descriptive variables; outcomes were summarized descriptively. Results: 10 retrospective studies met inclusion criteria. Pooled mean age was 61 years (95% CI 57.18–65.17) with male predominance (58%, 95 CI 53–63). TP53 m were uncommon in patients with Ph-negative MPN (3%, 95% CI 0–15%) but were higher in MF/AP/BP (10%, 95% CI 4–24%). Among patients with TP53 m, disease distribution included MF (35%, 95% CI 13–65%), AP/BP (33%, 95% CI 26–41%), essential thrombocythemia (ET) (10%, 95% CI 3–28%), and polycythemia vera (PV) (8%, 95% CI 4–14%). Multi-hit TP53 m accounted for 52% (95% CI 40–64%), while single-hit comprised 47% (95% CI 34–60%). The pooled mean TP53 VAF was 37.48% (95% CI 30.73–44.24%). Allo-HCT was used in 16% (95% CI 13–20%). One cohort reported leukemic transformation in 47% with a median follow-up of 9.6 months (m). Reported mOS in TP53 m CP-MF ranged from 11.6–18 m and was not reached in PV/ET, whereas AP/BP mOS ranged from 4.5–6 months. Conclusions: TP53 m Ph–negative MPNs are enriched in MF and AP/BP and frequently demonstrate multi-hit TP53 m with high VAF and associated with high leukemic transformation. Standardized molecular reporting and prospective studies are needed to refine prognostication and treatment strategies in TP53m MPN. Characteristics of patients with TP53 m MPN. Variable Pooled variables (95% CI) Age 61.18 years (57.18–65.17) Male/Female 58% (53–63)/42% (53–63) TP53 mutation in the cohort 3% (0–15) TP53 in MF/AP/BP 10% (CI 4–24) Primary myelofibrosis 35% (13–65) MPN in AP/BP 33% (26–41) Essential thrombocythemia 10% (CI 3–28) Polycythemia vera 8% (CI 4–14) Multi-hit/single-hit TP53 52% (CI 40–64) 47% (CI 34–60) TP53 VAF 37.48% (30.73–44.24) Abbreviations: MF: Myelofibrosis, AP: accelerated phase, BP: Blast phase, MPN: myeloproliferative neoplasm, VAF: Variant Allele Frequency.

e18579 Background: Outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) are often summarized using overall survival (OS) or treatment related mortality (TRM), which may obscure distinct biologic and toxicity driven pathways of failure. Major organ toxicities are important causes of morbidity and mortality but are rarely evaluated as competing events alongside relapse. We sought to characterize relapse and major organ failure as distinct competing pathways after allo-HCT. Methods: We analyzed adult allo-HCT recipients from the CIBMTR RT17-01 publicly available dataset (2008-2016). The primary endpoint was the first post transplant failure pathway, defined as relapse, major organ failure (MOF) requiring dialysis or diagnosed as thrombotic microangiopathy (TMA), veno-occlusive disease (VOD), or idiopathic pneumonia syndrome (IPS), or death without prior relapse or MOF. Competing risk methods estimated cumulative incidence, and cause specific Cox models evaluated associations between conditioning intensity and outcomes, adjusting for clinical and transplant related covariates, with the renal component of the hematopoietic cell transplantation comorbidity index (HCT-CI) removed. Results: The cohort included 13,187 adult recipients with a median age of 58.6 years, of whom 59.3 percent were male. Conditioning intensity was myeloablative (MAC) in 6,134 patients, reduced intensity (RIC) in 4,795, and non myeloablative (NMA) in 2,221. The first failure pathway was relapse in 5,157 patients, MOF in 1,511, and death without relapse or MOF in 2,535. At one year, cumulative incidence was 32.4 percent for relapse, 10.4 percent for MOF, and 13.1 percent for death without either event. IPS and dialysis requiring renal failure were the most frequent MOF events. Compared with MAC, RIC was associated with higher relapse risk (adjusted hazard ratio [aHR] 1.14; 95 percent confidence interval [CI] 1.07-1.23) and lower MOF risk (aHR 0.72; 95 percent CI 0.64-0.82). NMA conditioning showed a further shift toward relapse (aHR 1.42; 95 percent CI 1.30-1.54) with greater reduction in MOF risk (aHR 0.55; 95 percent CI 0.46-0.66). Conclusions: Relapse and MOF represent distinct competing pathways of failure after allo-HCT. Conditioning intensity influences which pathway predominates, with less intensive regimens shifting risk from organ toxicity toward relapse. Pathway based competing risk analyses provide insight beyond traditional survival endpoints and may support more individualized transplant decision making.

e18574 Background: ND has historically been recommended to reduce infectious complications in cancer patients (pts). While the adoption of ND has declined over the last decade, recent studies - particularly in pts undergoing hematopoietic stem cell transplantation (HSCT) - have raised uncertainty regarding the safety of LD. Herein, we performed a meta-analysis of studies directly comparing ND with LD in pts with cancer. Methods: We conducted a systematic search of MEDLINE, Embase, and Cochrane databases from inception through January 2026. Comparative retrospective and prospective studies were included if they were comparing ND with LD in adults or children with cancer. Primary outcomes were major infections and bacteremia/fungemia. Secondary outcomes were pneumonia, diarrhea, and all-cause mortality. Random-effects meta-analyses were performed to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). The review followed PRISMA 2020 guidelines. Results: Fifteen studies enrolling 4,320 patients were included in the primary analysis. Six studies enrolled only adult patients, three were restricted to pediatric populations, and six included mixed adult and pediatric cohorts. Across these studies, ND was not associated with a significant reduction in major infections (RR 1.02, 95% CI 0.88–1.18; p=0.795), bacteremia/fungemia (RR 0.97, 95% CI 0.78–1.22; p=0.805), pneumonia (RR 0.98, 95% CI 0.59–1.63; p=0.933), diarrhea (RR 1.12, 95% CI 0.96–1.31; p=0.159), or all-cause mortality (RR 0.94, 95% CI 0.77–1.15; p=0.632). Sensitivity analyses restricted to RCTs showed consistent results. Subgroup analysis of hematological/HSCT studies (9 studies; 1,769 pts) also showed no differences across outcome. Analysis restricted to RCTs in hematologic/HSCT pts (6 studies; 855 pts) showed no differences in major infections, pneumonia, diarrhea, or mortality; however, ND was associated with a lower risk of bacteremia/fungemia (RR 0.67, 95% CI 0.47–0.95; p=0.023). Heterogeneity across studies was low to moderate. Conclusions: ND was not associated with reductions in major infections, pneumonia, diarrhea, or mortality compared with LD. A reduction in bacteremia/fungemia was observed in RCTs of hematologic malignancy and HSCT pts. Overall, these findings suggest that routine ND implementation is unnecessary for most cancer pts, although cautious dietary practices may remain reasonable in selected high-risk hematologic malignancy/HSCT populations.

e18542 Background: Outcomes in adult acute lymphocytic leukemia (ALL) remain heterogeneous and strongly influenced by age. However, population-level survival gradients across older age strata and the future burden of disease in an aging population remain incompletely characterized. We evaluated long-term survival patterns and projected disease burden in adult ALL using national registry data. Methods: We conducted a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database including adults aged 50–89 years diagnosed with ALL between 2000 and 2022. Overall survival (OS) was estimated using Kaplan–Meier methods and compared across age and racial subgroups. Multivariable Cox proportional hazards regression was performed to identify independent predictors of mortality. Temporal trends in annual case counts were analyzed and projected through 2035 using time-series forecasting methods. Results: A total of 7,298 adult ALL patients were included. OS declined progressively with advancing age, demonstrating clear stepwise separation across age strata. Compared with patients aged 50–54 years, mortality risk increased incrementally across successive age groups, reaching more than fourfold higher risk among patients aged 85–89 years on multivariable analysis. Race-based survival differences were observed on unadjusted analysis; however, these differences were attenuated after adjustment for age and clinical factors. More recent year of diagnosis was independently associated with modest survival improvement, reflecting incremental therapeutic progress. Forecasting analysis projected a continued rise in adult ALL case burden through 2035, with widening uncertainty intervals over time, indicating sustained future healthcare impact. Conclusions: Adult ALL outcomes remain strongly age dependent, with sharply escalating mortality risk among older patients despite gradual therapeutic improvements. Projections indicate a sustained and growing disease burden in the United States. These findings highlight the urgent need for age-adapted treatment strategies, improved inclusion of older adults in clinical trials, and healthcare system preparedness to address the needs of an aging leukemia population.

e18536 Background: Nucleophosmin 1 (NPM1) mutation is traditionally associated with a favorable prognosis in acute myeloid leukemia (AML), leading to classification of these patients within the European LeukemiaNet (ELN) favorable risk group. However, emerging evidence indicates that co-occurring secondary-type mutations (STMs), including ASXL1 , RUNX1 , EZH2 , and SRSF2 , may substantially modify this prognosis. While meta-analyses have quantified the relative risk associated with STMs using hazard ratios, the corresponding absolute survival impact remains unclear, limiting clinical interpretability and decision-making. Methods: We performed meta-analysis–based projection modeling using pooled overall survival hazard ratios reported in a recent systematic review and meta-analysis of 4,022 NPM1-mutated AML patients. For the ELN-favorable subgroup, the pooled hazard ratio for overall survival associated with STMs (HR 1.95; 95% CI 1.39–2.73) was combined with externally derived baseline 5-year survival estimates under a proportional hazards framework. Absolute survival probabilities were calculated using established survival–hazard transformations, and results were translated into projected outcomes for a hypothetical cohort of 1,000 future ELN-favorable NPM1-mutated AML patients. Uncertainty was quantified using the meta-analytic confidence interval. Results: Assuming a baseline 5-year overall survival of 70% for ELN-favorable NPM1-mutated AML patients without STMs, the presence of STMs was projected to reduce 5-year survival to approximately 50%. Based on the confidence interval of the pooled hazard ratio, projected survival with STMs ranged from 38% to 61%. In a simulated cohort of 1,000 patients, this corresponds to approximately 300 deaths at 5 years in the absence of STMs versus 501 deaths in the presence of STMs, yielding an estimated 200 excess deaths per 1,000 patients (plausible range: 90–320 excess deaths). These findings were robust across visualizations including absolute survival projections, stacked outcome distributions, and excess mortality estimates. Conclusions: Meta-analysis–based projection modeling demonstrates that secondary-type mutations may negate much of the favorable prognosis traditionally attributed to ELN-favorable NPM1-mutated AML, translating into a large absolute survival decrement in future patient cohorts. Converting relative risk estimates into absolute survival and event projections provides clinically actionable insight and supports the incorporation of secondary-type mutation status into risk stratification, trial design, and therapeutic decision-making.

e18524 Background: Venetoclax (Ven) in combination with hypomethylating agents (HMA) is FDA-approved front-line therapy for elderly or unfit patients with newly-diagnosed acute myeloid leukemia (ND-AML); however, majority relapse or are refractory ( Pratz AJH 2024 ). We examined survival outcomes in the setting of frontline Ven-HMA failure. Methods: ND-AML patients with failure to achieve complete remission (CR/CRi) or loss of CR/CRi after front-line Ven+HMA, excluding post-transplant relapse were retrospectively studied. Response was evaluated per European Leukemia Net 2022 criteria ( Dohner Blood 2022 ). Results: 356 patients with ND-AML (median age 75 years; 65% males; 55% secondary) receiving frontline Ven+HMA (median; 3 cycles (1-26), had refractory [n=219 (62%)], or relapsed disease [137 (38%)]. At diagnosis, karyotype was complex in 142/347 (41%). Mutations involved TP53 (29)%, ASXL1 (19%), RUNX1 (17%), SRSF2 (15%), KRAS/NRAS (13%), IDH2 (7%), FLT3-ITD (7%), NPM1 (6%) and IDH1 (5%). At treatment failure, complex karyotype was present in 72/180 (40%), including 55 from baseline. In 137 patients with paired NGS, mutations persisted in TP53 (88%), IDH1 (86%), IDH2 (78%), NPM1 (75%), K/NRAS (73%), RUNX1 (70%), FLT3-ITD (65%) mutations. Mutations were acquired in a minority [ IDH1 / IDH2 (2% each) TP53 (3%), NPM1 (4%), FLT3-ITD (5%) K/NRAS (6%)]. Clearance of mutations were infrequent for TP53 (12%) and IDH1 (14%). At median follow-up of 4 months (mo) (0-80) from the time of relapse/refractory disease, 320 (90%) patients have died, with median survival of 4 mo (1-2-3 yr survival 19%/8%/5%). On multivariate analysis, peripheral blasts >20%, complex karyotype, and wild-type IDH1 were independent predictors of inferior survival, while allogeneic stem cell transplant (ASCT) was associated with improved survival. A 3-point prediction model based on peripheral blasts ≥20%, complex karyotype, and wild-type IDH1 stratified patients into low-, intermediate-, and high-risk groups, with median survival of 7, 3, 2 months, respectively (p<0.01). 13 patients underwent ASCT (median survival; 22.5 mo; 3-yr survival 33%), from low (n=10) or intermediate-risk groups (n=3). Salvage therapy (n=170, 48%) yielded CR/CRi of 31% for Ven+HMA (n=36), 54% intensive chemotherapy (n=26), 50% FLT3 inhibitors (i) (n=22), 37% IDH1/2i (n=19), 25% other regimens (n=69). Median survival was similar: Ven+HMA 8 mo, intensive chemotherapy 10 mo, FLT3i 6.5 mo, IDH1/2i 14 mo, other regimens 6 mo, but inferior with supportive care (2 mo; p<0.01). Conclusions: The current study identifies peripheral blasts ≥20%, complex karyotype, and wild-type IDH1 as predictors of inferior survival in ND-AML relapsed/refractory to front-line Ven+HMA and underlines that while no specific salvage therapy conferred superior outcomes, ASCT was indispensable for long-term survival.

e18149 Background: Laryngeal neuroendocrine carcinoma (LNEC) is rare and biologically heterogeneous. The independent prognostic roles of tumor differentiation and stage remain incompletely defined. Methods: Patients diagnosed with LNEC (2000–2022) were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were estimated using a Kaplan–Meier analysis. Tumor differentiation (Diff) was harmonized across SEER grade fields: legacy Grade Recode (through 2017) was used when available; otherwise, Grade Clinical/Pathological (2018+) codes (1=well, 2=moderate, 3=poor, 4=undifferentiated) defined Diff. Multivariable Cox regression adjusted for stage, Diff, age, and sex. Cases with missing survival time, stage, or Diff were excluded (n=97). Results: The cohort included 157 patients (median age 63 years; 63% male). Diff was well in 4%, moderate in 29%, poor in 34%, and undifferentiated in 12% of patients. At diagnosis, 22% of patients had localized, 27% had regional, and 28% had distant disease. Treatments included surgery in 31%, chemotherapy in 42%, and adjuvant radiation in 13% of patients. Median OS differed significantly by Diff, ranging from 52.5 months (mo) for well, 90 mo for moderate, 12 mo for poor, and 17 mo for undifferentiated (p<0.001). Five-year OS was 50%, 58%, 23%, and 37%, respectively, with a similar gradient for CSS (p=0.001). Survival remained differentiation-associated within surgical (p=0.004) and chemotherapeutic subgroups (p<0.001). Median OS by stage was 96 mo for localized disease, 30 mo for regional nodes only, 8.5–7.5 mo for regional direct extension ± nodes, and 11 mo for distant disease. On multivariable analysis, stage and differentiation—driven primarily by poorly differentiated tumors—were independently associated with OS. Conclusions: Both tumor differentiation and stage independently predicted survival in LNEC, indicating that tumor biology and anatomic extent each contribute to prognosis. Outcomes remain suboptimal in poorly differentiated and advanced-stage LNEC, underscoring the need for treatment optimization and clinical trial development. Variable HR (95% CI) p Differentiation (Diff) Moderate vs Well 1.76 (0.49–6.31) 0.39 Poor vs Well 6.11 (1.63–22.93) 0.007 Undifferentiated vs Well 2.28 (0.60–8.76) 0.23 Stage Nodes only vs Localized 2.21 (1.14–4.38) 0.023 Direct extension only vs Localized 14.04 (2.44–80.97) 0.003 Direct + nodes vs Localized 7.49 (3.19–17.63) <0.001 Distant vs Localized 3.34 (1.63–6.83) 0.001 Male vs Female 2.28 (1.34–3.89) 0.002

e18060 Background: Intensity-modulated proton therapy (IMPT) has been gaining popularity as a method of treating locally advanced HPV positive oropharyngeal squamous cell carcinoma (OPSCC) due to the ability to reduce the amount of normal tissue that is exposed to radiation but whether or not it will result in better clinical outcomes when compared to intensity-modulated photon radiotherapy (IMRT), is still unknown. We performed a meta-analysis to evaluate the effects of IMPT on both cancer related toxicities and outcomes in comparison to IMRT for patients diagnosed with locally advanced HPV positive OPSCC. Methods: We evaluated all comparative studies that examined the use of IMPT vs. IMRT in stage III-IV HPV positive OPSCC. Using random-effects models, we estimated pooled relative risks (RRs) with 95% CIs for each study's measure of association. The primary outcomes of interest were: weight loss; gastrostomy tube insertion; xerostomia; dysphagia; mucositis; fatigue; locoregional recurrence; and OS. Statistical heterogeneity was assessed via I². Results: In total, there were 4 studies that involved 912 patients. As per these studies, a greater number of patients experienced clinically relevant weight loss when receiving IMPT than when receiving IMRT (RR 1.63, 95% CI 1.17–2.27; p= .004; I²= 0%). Additionally, a comparison of six studies which included a total of 1143 patients indicated that gastrostomy tubes are inserted more often after IMPT (RR 2.9, 95% CI 1.8 – 4.6; p<.00001; I²= 0%). No statistically or clinically significant differences were found regarding other side effects from treatments. In terms of cancer recurrence, there was a greater rate of loco-regional recurrence for those patients who received IMPT as compared to IMRT (RR 1.58, 95% CI 1.26- 1.97; p< .0001; I²= 0%) in three studies which included a total of 592 patients. However, no statistical difference in overall survival was identified between IMPT and IMRT (RR 1.06, 95% CI 0.87- 1.29; p=.56), even though there was significant variability (I²= 87%) in three studies which included a total of 747 patients. Conclusions: In locally advanced HPV positive OPSCC, there were no differences in toxicity profiles from IMPT compared to IMRT, and there were increased rates of weight loss, gastrostomy tube placement, and locoregional recurrence from IMPT compared to IMRT, without any observed survival advantage. This highlights the need for future prospective randomized trials to clarify the role of IMPT in the management of locally advanced HPV positive OPSCC.