Background: Mixed phenotype acute leukemia (MPAL) is a rare and heterogeneous subtype of acute leukemia. Per the 2022 WHO criteria, it is categorized based on its predominant immunophenotypic lineage (B vs. T) and the presence of a Philadelphia chromosome (Ph+) or a KMT2A rearrangement. While many other cytogenetic and molecular abnormalities have been described, due to the rarity of this disease, neither their incidence nor the role of targeted therapies has been well defined. We conducted a retrospective study of all veterans with MPAL diagnosed between 2000-2023 to examine the impact of different clinical, immunophenotypic, cytogenetic, molecular, and treatment strategies on overall survival (OS). Methods: Electronic medical record data from the Veterans Affairs Informatics and Computing Infrastructure database were used to identify 320 patients diagnosed with MPAL between 2000-2023 using the text utilization integration feature to query all notes. All patient charts were reviewed manually. Pathology reports and clinical notes were reviewed to collect data on diagnosis, treatment, and outcome. To date, 74 patients have been identified and included in this preliminary analysis. Cox regression analyses were used to compare OS between patients with different MPAL subtypes, cytogenetic, and molecular features as well as different treatment approaches. Multivariate analysis was performed with controls for age, race, and BMI. Results: In line with prior research, decreases in OS were seen among older patients > 65 yo compared to patients <30 yo and those who received an AML induction over ALL induction regimen with HR of 8.28 (p 0.04) and 2.02 (p 0.03) respectively. Patients who had a transplant had significantly improved OS with a HR of 0.19 (p <0.001). Of the 32 patients who had potentially targetable mutations, 14 received targeted maintenance therapy with either Ph+ or FLT3 inhibitors. Patients who got targeted maintenance therapy (including FLT3 inhibitors) had an OS of 55 months compared to 17 months for those who did not. 50% of those patients who did not get maintenance therapy went to transplant and 31% of patients who did get maintenance therapy went to transplant yet these patients still had improved OS. Conclusions: This preliminary data demonstrate that while MPAL is a complex and heterogeneous disease, a significant portion of patients have targetable mutations. Further studies evaluating targeted therapies such as FLT3, IDH, and menin inhibitors in MPAL patients may be warranted.