Alhusari, Leena

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.

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.

Abstract Zieve's syndrome is a rare and often overlooked complication of alcohol misuse, likely under-recognized due to limited physician awareness. We present a unique case with an atypical and misleading clinical presentation that initially raised concern for a hepatic mass. Despite the diagnostic uncertainty, the astute clinical vigilance and thoughtful evaluation by the treating team led to the correct diagnosis of Zieve's syndrome. This case highlights the importance of maintaining a broad differential and considering alcohol-related syndromes even when initial findings suggest alternative etiologies. We present the case of a 29-year-old man with a history of essential tremor managed on propranolol, who was transferred for further evaluation of worsening jaundice following a brief, self-resolving viral-like illness. He denied abdominal pain, ongoing gastrointestinal symptoms, intravenous drug use, or alcohol intake. Initial CT abdomen/pelvis showed hepatic steatosis and a 4.5 × 2.5 × 7.0 cm lobulated hypodense lesion in the right hepatic lobe, raising concern for pyogenic abscess versus neoplasm. Gallbladder wall was mildly thickened (5 mm) without pericholecystic fluid or biliary dilation. He was transferred for further evaluation. Laboratory evaluation revealed macrocytic anemia (Hb 9.9 g/dL, MCV 102 fL), thrombocytopenia (PLT 148), markedly elevated bilirubin (total 12.9 mg/dL, direct 6.8 mg/dL), transaminitis (ALT 93 U/L, AST 217 U/L), and evidence of hemolysis with low haptoglobin (30 mg/dL), elevated LDH (339 U/L), and a low reticulocyte count (0.39%). Sodium was 127 mmol/L, and INR was normal. Hepatitis viral panel, urine drug screen, and urinalysis were negative. Lipid panel revealed extreme hyperlipidemia with triglycerides 1500 mg/dL, LDL 687 mg/dL, and total cholesterol 1300 mg/dL. Peripheral smear showed macrocytic anemia with mild anisocytosis, slight polychromasia, and mild red blood cell agglutination. RUQ ultrasound showed hepatic steatosis with no focal lesion. MRI liver protocol revealed hepatomegaly and diffuse hepatic steatosis with sparing in the falciform ligament, gallbladder fossa, and portions of the right hepatic lobe explaining the CT “lesion” as focal fat sparing rather than a true mass. Although the patient denied alcohol misuse, phosphatidylethanol (PEth) testing was positive, confirming recent heavy alcohol consumption. The clinical picture was consistent with alcohol-associated liver injury, hemolysis, and secondary hyperlipidemia. In conclusion, Zieve's syndrome is characterized by a triad of hemolytic anemia, cholestatic jaundice, and transient hyperlipidemia. Prompt recognition of this underdiagnosed condition is crucial, as it can prevent unnecessary invasive interventions and shift the clinical focus toward supportive care and alcohol cessation, which remains the cornerstone of treatment.